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Evidence of popular interest in the interrelationships between mind, body, and heart disease dates to Ancient Grecian times and paved the way for modern-day scientific inquiry into the relationships between psychological comorbidities in coronary heart disease. Although the systematic evidence has suggested an association of poor medical prognosis and lower quality of life among patients with coronary heart disease with comorbid psychological conditions, the mechanisms are less well understood. In this selective review article, the epidemiology, mechanisms, screening, and treatment recommendations for 4 common psychological conditions (depression, anxiety, stress, and insomnia) comorbid with coronary heart disease are presented. We focus on the grand challenges and unprecedented opportunities for research in this area considering the methodological and technological innovations of the 21st century.