Comorbidities are present in greater than 75% of cardiac patients. While choosing therapy for such patients it is important to keep in mind the complex interactions of various drugs in the background of comorbidities. Safety should be the prime concern though the efficacy of the drugs should not be compromised too much. This article touches upon the therapy of cardiac patients with anemia, diabetes mellitus, kidney disease, thyroid disorders, sleep disorders, psychiatric illness, or malignancies. Drug class, dosage, drug route, or contraindications have been highlighted for optimal management.