Obesity leads to persistent increases in immune responses that contribute to cardiometabolic pathologies such as diabetes and cardiovascular disease. Pro-inflammatory macrophages infiltrate the expanding fat mass, which leads to increased production of cytokines such as tumor necrosis factor-alpha. Moreover, saturated fatty acids enhance signaling through the toll-like receptors involved in innate immunity. Herein we discuss the evidence that ceramides-which are intermediates in the biosynthetic pathway that produces sphingolipids-are essential intermediates that link these inflammatory signals to impaired tissue function. We discuss the mechanisms linking these immune insults to ceramide production and review the numerous ceramide actions that alter cellular metabolism, induce oxidative stress, and stimulate apoptosis. Lastly, we evaluate the correlation of ceramides in humans with inflammation-linked cardiometabolic disease and discuss preclinical studies which suggest that ceramide-lowering interventions may be an effective strategy to treat or prevent such maladies.