Heart failure is associated with a range of comorbidities that have the potential to impair both quality of life and clinical outcome. Unfortunately, noncardiac diseases are underrepresented in large randomized clinical trials, and their management remains poorly understood. In clinical practice, the prevalence of comorbidities in heart failure is high. Although the prognostic impact of comorbidities is well known, their prevalence and impact in specific heart failure settings have been overlooked. Many studies have described specific single noncardiac conditions, but few have examined their overall burden and grading in patients with multiple comorbidities. The risk of comorbidities in patients with heart failure rises with more advanced disease, older age, and increased frailty—three conditions that are poorly represented in clinical trials. The pathogenic links between comorbidities and heart failure involve many pathways and include neurohormonal overdrive, inflammatory activation, oxidative stress, and endothelial dysfunction. Such interactions may worsen prognoses, but details of these relationships are still under investigation. We propose a shift from cardiac-focused care to a more systemic approach that considers all noncardiac diseases and related medications. Some new drugs class such as ARNI or SGLT2 inhibitors could change prognosis by acting directly or indirectly on metabolic disorders and related vascular consequences.