Children with oppositional defiant disorder (ODD) and a concurrent Axis I diagnosis are often prescribed drug therapy for attention deficit hyperactivity disorder (ADHD) to manage disruptive behavior. However, ODD symptoms tend to be poorly controlled, raising questions about the effectiveness of drug therapy in children with the condition. Safety and long term consequences of pharmacological agents for ODD are important factors clinicians must consider before initiating treatment. The purpose of this literature review is to examine the pharmacodynamics and efficacy of drug therapy used for ODD in school-age children and adolescents. Additionally, awareness of poor behavior patterns and recognition of symptoms associated with ODD in children among health care providers was explored. A literature review exploring ODD and drug therapy for ODD and related behavioral disorders was conducted from various online databases. Results from 15 reviewed studies suggest that pharmacologic therapy is typically prescribed for ODD symptoms when a comorbid condition such as ADHD, a mood disorder, or an anxiety disorder is present. Drug therapy for ADHD has demonstrated effective behavioral outcomes in reducing ODD symptom severity in children and tolerable side effects when used for short-term therapy. Studies have demonstrated success and better control of ODD symptoms with a focused drug therapy regimen. Overall, the benefits of drug therapy can potentially outweigh the risks of adverse effects, and improve the quality of life in children with ODD. In conclusion, uncovering the reasons for poorly controlled ODD in children can be of clinical significance to health care providers and can support decision making when considering drug therapy for children with this condition.