Chronic heart failure is one of the most common causes of hospitalization and death in industrialized countries. Demographic changes with an aging population are expected to further increase the prevalence of chronic heart failure. The associated increase in comorbidities in patients with chronic heart failure leads to a less favorable prognosis for survival. A selection of the major comorbidities discussed in this review—along with prevalence, impact on prognosis, treatment approaches, and current study status—include atrial fibrillation, arterial hypertension, coronary artery disease, coronary microvascular dysfunction, renal dysfunction, type 2 diabetes, sleep apnea, reduced lymphatic reserve, and the effects on oxygen utilization and physical activity. The complex clinical picture of heart failure with preserved ejection fraction (HFpEF) remains challenging in the nearly absence of evidence-based therapy. Except for comorbidity-specific guidelines, no HFpEF-specific treatment of comorbidities can be recommended at this time. Optimized care is becoming increasingly relevant to reducing hospitalizations through a seamless inpatient and outpatient care structure. Current treatment is focused on symptom relief and management of associated comorbidities. Therefore, prevention through early minimization of risk factors currently remains the best approach.