To understand the contribution of adipose tissue fatty acid oxidation to whole-body metabolism, we generated mice with an adipose-specific knockout of carnitine palmitoyltransferase 2 (CPT2^A−/−), an obligate step in mitochondrial long-chain fatty acid oxidation. CPT2^A−/− mice became hypothermic after an acute cold challenge, and CPT2^A−/− brown adipose tissue (BAT) failed to upregulate thermogenic genes in response to agonist-induced stimulation. The adipose-specific loss of CPT2 resulted in diet-dependent changes in adiposity but did not result in changes in body weight on low- or high-fat diets. Additionally, CPT2^A−/− mice had suppressed high-fat diet-induced oxidative stress and inflammation in visceral white adipose tissue (WAT); however, high-fat diet-induced glucose intolerance was not improved. These data show that fatty acid oxidation is required for cold-induced thermogenesis in BAT and high-fat diet-induced oxidative stress and inflammation in WAT.