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Acute-onset heart failure in a young, otherwise healthy patient can be due to either acquired or congenital etiologies. While some diagnoses carry specific histologic hallmarks, many causes of myocardial injury culminate in the relatively nonspecific morphologic pattern of dilated cardiomyopathy. In such cases, a broad differential diagnosis and close clinicopathologic correlation are essential. Here we describe the acute and chronic histologic features of heart failure arising in the context of long-standing abuse of cocaine, alcohol, and marijuana. The mechanisms of cardiotoxicity are discussed for each drug, with particular emphasis on the amplified cardiac injury caused by concomitant cocaine and alcohol use. Although its histologic features are themselves nonspecific, correlation with clinical history, targeted studies to exclude alternative diagnoses, and careful morphologic examination permit confident diagnosis of cardiomyopathy secondary to polysubstance abuse.