Compliance has become a topic of intense investigation and debate during the past two decades. The present review first examines to what factors the exponential increase in research studies on the topic can be attributed. A second part summarizes the history of the concept, the definitions and measurements of compliance and the estimations of compliance and non-compliance. Studies searching for relevant components of compliance behavior can be divided in two groups. A first group of publications originates from a biomedical and pharmaceutical approach, and investigates which characteristics of illness, of drug regimen or drug side effects, of patients, doctors or their practices can predict the variance in compliance. The implicit aim of these studies is the development of strategies leading to increased compliance. A second group of publications originates from medical psychology (psychodynamic, cognitive-behavior and interactional considerations) and investigates why a given patient is compliant or not, sometimes even suggesting that non-compliance can even be a meaningful response. The present review suggests that the relation between the occurrence of side effects and non-compliance during treatment with antidepressant drugs is more complex than usually accepted and that, in case of non-compliance, finding an equilibrium between authoritarian tactics and passive avoidance does remain one of the challenges in daily practice.