Across the United States, Human Anatomy and Physiology (HA&P) courses typically have some of the highest withdrawal and failure rates on college campuses. These high enrollment course typically serve as gate-keepers for those individuals with aspirations of entering the medical field. In light of the growing national shortage of healthcare professionals, there is a pressing need to improve the state of HA&P education at a national scale. The goal of this dissertation is to understand why undergraduate students struggle to succeed in HA&P courses. I leveraged multiple frameworks from biology education research, physics education research, and cognitive psychology to understand the source of student difficulty in HA&P. I used a mixed-methods approach to unpack how students reason about the complex phenomena covered in HA&P classes. The data presented here suggest student difficulties in HA&P are not the product of a culmination of individual conceptual difficulties. Rather, this work suggests students have difficulty reasoning with the many complex systems that are at the heart of HA&P curriculum. Students appear to frame these complex systems in a manner that activates reasoning strategies that are often in conflict with course goals. The findings from this work advocate for a dynamic view of student cognition that recognizes the implications of context features on student reasoning of complex systems.