Background: Joint stability has been experimentally and clinically linked to mechanisms of knee injury and joint degeneration. The only dynamic, and perhaps most important, regulators of knee joint stability are contributions from muscular contractions. In participants with unstable knees, such as anterior cruciate ligament (ACL) injured, a range of neuromuscular adaptations has been observed including quadriceps weakness and increased co-activation of adjacent musculature. This co-activation is seen as a compensation strategy to increase joint stability. In fact, despite increased co-activation, instability persists and it remains unknown whether observed adaptations are the result of injury induced quadriceps weakness or the mechanical instability itself. Furthermore, there exists conflicting evidence on how and which of the neuromuscular adaptations actually improve and/or reduce knee joint stability. Purpose: The overall aim of this thesis is therefore to elucidate the role of injury and muscle weakness on muscular contributions to knee joint stability by addressing two main objectives: (1) to further our understanding of individual muscle contribution to internal knee joint moments; and (2) to investigate neuromuscular adaptations, and their effects on knee joint moments, caused by either ACL injury and experimental voluntary quadriceps inhibition (induced by pain). Methods: The relationship between individual muscle activation and internal net joint moments was quantified using partial least squares regression models. To limit the biomechanical contributions to force production, surface electromyography (EMG) and kinetic data was elicited during a weight-bearing isometric force matching task. A cross-sectional study design determined differences in individual EMG-moment relationships between ACL deficient and healthy controls (CON) groups. A crossover placebo controlled study design determined these differences in healthy participants with and without induced quadriceps muscle pain. Injections of hypertonic saline (5.8%) to the vastus medialis induced muscle pain. Isotonic saline (0.9%) acted as control. Effect of muscle pain on muscle synergies recruited for the force matching task, lunging and squatting tasks was also evaluated. Synergies were extracted using a concatenated non-negative matrix factorization framework. Results/Discussion: In CON, significant relationships of the rectus femoris and tensor fascia latae to knee extension and hip flexion; hamstrings to hip extension and knee flexion; and gastrocnemius and hamstrings to knee rotation were identified. Vastii activation was independent of moment generation, suggesting mono-articular vastii activate to produce compressive forces, essentially bracing the knee, so that bi-articular muscles crossing the hip can generate moments for the purpose of sagittal plane movement. Hip ab/adductor muscles modulate frontal plane moments, while hamstrings and gastrocnemius support the knee against externally applied rotational moments. Compared to CON, ACL had 1) stronger relationships between rectus femoris and knee extension, semitendinosus and knee flexion, and gastrocnemius and knee flexion moments; and 2) weaker relationships between biceps femoris and knee flexion, gastrocnemius and external knee rotation, and gluteus medius and hip abduction moments. Since the knee injury mechanism, is associated with shallow knee flexion angles, valgus alignment and rotation, adaptations after ACL injury are suggested to improve sagittal plane stability, but reduce frontal and rotational plane stability. During muscle pain, EMG-moment relationships of 1) semitendinosus and knee flexor moments were stronger compared to no pain, while 2) rectus femoris and tensor fascia latae to knee extension moments and 3) semitendinosus and lateral gastrocnemius to knee internal rotation moments were reduced. Results support the theory that adaptations to quadriceps pain reduces knee extensor demand to protect the joint and prevent further pain; however, changes in non-painful muscles reduce rotational plane stability. Individual muscle synergies were identified for each moment type: flexion and extension moments were respectively accompanied by dominant hamstring and quadriceps muscle synergies while co-activation was observed in muscle synergies associated with abduction and rotational moments. Effect of muscle pain was not evident on muscle synergies recruited for the force matching task. This may be due to low loading demands and/or a subject-specific redistribution of muscle activation. Similarly, muscle pain did not affect synergy composition in lunging and squatting tasks. Rather, activation of the extensor dominant muscle synergy and knee joint dynamics were reduced, supporting the notion that adaptive response to pain is to reduce the load and risk of further pain and/or injury. Conclusion: This thesis evaluated the interrelationship between muscle activation and internal joint moments and the effect of ACL injury and muscle pain on this relationship. Findings indicate muscle activation is not always dependent on its anatomical orientation as previous works suggest, but rather on its role in maintaining knee joint stability especially in the frontal and transverse loading planes. In tasks that are dominated by sagittal plane loads, hamstring and quadriceps will differentially activate. However, when the knee is required to resist externally applied rotational and abduction loads, strategies of global co-activation were identified. Contributions from muscles crossing the knee for supporting against knee adduction loads were not apparent. Alternatively hip abductors were deemed more important regulators of knee abduction loads. Both muscle pain and ACL groups demonstrated changes in muscle activation that reduced rotational stability. Since frontal plane EMG-moment changes were not present during muscle pain, reduced relationships between hip muscles and abduction moments may be chronic adaptions by ACL that facilitate instability. Findings provide valuable insight into the roles muscles play in maintaining knee joint stability. Rehabilitative/ preventative exercise interventions should focus on neuromuscular training during tasks that elicit rotational and frontal loads (i.e. side cuts, pivoting maneuvers) as well as maintaining hamstring balance, hip abductor and plantarflexor muscle strength in populations with knee pathologies and quadriceps muscle weakness.