Obesity and insulin resistance are associated with ectopic lipid deposition in multiple tissues, including the heart. Excess lipid may be stored as triglycerides, but are also shunted into non-oxidative pathways that disrupt normal cellular signaling leading to organ dysfunction and in some cases apoptosis, a process termed lipotoxicity. Various pathophysiological mechanisms have been proposed to lead to lipotoxic tissue injury, which might vary by cell type. Specific mechanisms by which lipotoxicity alter cardiac structure and function are incompletely understood, but are beginning to be elucidated. This review will focus on mechanisms that have been proposed to lead to lipotoxic injury in the heart and will review the state of knowledge regarding potential causes and correlates of increased myocardial lipid content in animal models and humans. We will seek to highlight those areas where additional research is warranted. © 2009 Elsevier B.V. All rights reserved.