Cardiolipin is a specialized phospholipid found primarily in the inner mitochondrial membrane. Because of its unique dimeric structure, cardiolipin plays an important role in mitochondrial function, stability, and membrane fluidity. As such, cardiolipin is subject to a high degree of remodeling by phospholipases, acyltransferases, and transacylases that create a fatty acyl profile that tends to be highly tissue-specific. Despite this overarching regulation, the molecular species of cardiolipin produced are also influenced by dietary lipid composition. A number of studies have characterized the tissue-specific profile of cardiolipin species and have investigated the specific nature of cardiolipin remodeling, including the role of both enzymes and diet. The aim of this review is to highlight tissue specific differences in cardiolipin composition and, collectively, the enzymatic and dietary factors that contribute to these differences. Consequences of aberrant cardiolipin fatty acyl remodeling are also discussed.