Understanding the molecular mechanisms of insulin resistance remains a major medical challenge of the twenty-first century. Over the last half-century, many hypotheses have been proposed to explain insulin resistance, and, most recently, inflammation associated with alterations in adipocytokines has become the prevailing hypothesis. Here we discuss diacylglycerol-mediated insulin resistance as an alternative and unifying hypothesis to explain the most common forms of insulin resistance associated with obesity and type 2 diabetes mellitus, as well as lipodystrophy and aging.