We discuss the challenges of implementing clinical practice guidelines for depression in the primary care setting. Multiple potential barriers can limit physician guideline adherence and translation of research into improved patient outcomes. Six primary barriers relate to providers (lack of awareness, lack of familiarity, lack of agreement, lack of self efficacy, lack of outcome expectancy, and inertia of previous practice). In addition, factors related to patient, guideline, and practice environment factors encompass external barriers to adherence. By delineating the underlying barriers to adherence, different interventions that are tailored to improve physician adherence to guidelines can be utilized. We review examples of these barriers, as well as interventions to improve guideline adherence. We also review characteristics of successful interventions to improve physician adherence to guidelines for depression. Since different physicians and practice settings may encounter a variety of barriers, multifaceted interventions that are not focused exclusively on the physician tend to be most effective.