Chronic disease can severely impact an individual’s quality of life, influencing both physical and mental health. Major depressive disorder is one of the most common diagnoses among patients with physical conditions. Cognitive-behavioral therapy is a prominent evidence-based psychological treatment for depression. The objective of the present review is to summarize current research on the efficacy of this intervention in medically ill patients with comorbid depression. First, the relation between chronic disease and depression will be briefly described. Following this introduction, studies examining the efficacy of cognitive and behavioral techniques for reducing depressive symptoms in patients with frequent chronic diseases will be outlined. Subsequently, the effects of the psychological treatment for different patient populations will be analyzed. Finally, a few recommendations for adapting the intervention protocols to various target groups of people with specific characteristics will be provided in order to improve the mental health of patients with chronic medical conditions.