Macrophages are key members of the innate immune system. More recently, a preponderance of evidence suggest that macrophages play an important role in metabolic homeostasis. They are implicated in the pathogenesis of metabolic disorders such as type-2 diabetes and atherosclerosis. Human macrophages express SCD1, while rodent ones express both SCD1 and SCD2. Only a few studies have investigated the regulation of SCD1 expression in macrophages and reported that nuclear transcription factors regulate its expression. Of these, liver X receptor and retinoid X receptor increase SCD1 expression, while CCAAT-/enhancer-binding protein beta, farnesoid-X-receptor, and peroxisome proliferator-activated receptor gamma suppress it. Similar to its regulation in other tissues, stearoyl-CoA desaturase (SCD) expression in macrophages is repressed by polyunsaturated fatty acids (PUFA), especially omega-3 PUFA, via nuclear receptors. Lipid-laden macrophages, known as macrophage-derived foam cells, characterize the atherosclerotic lesion. Cholesterol efflux from these foam cells, especially via ATP-binding cassette transporter A1 (ABCA1), provides protection against the cholesterol accumulation in foam cells and further progression of the atherosclerotic plaque. Increased expression of SCD destabilizes ABCA1 and reduces cholesterol efflux in macrophages. Omega-3 PUFA can increase cholesterol efflux from foam cells through inhibition of SCD1. However, SCD inhibition in saturated fat-fed animals promotes, rather than suppresses, atherosclerosis in mouse models with hypercholesterolemia. This is attributed to the proinflammatory environment induced by saturated fatty acid-mediated toll-like receptor 4 activation in these models. Fish oil can ameliorate inflammatory responses and the atherosclerotic lesion development caused by SCD1 inhibition. Overall, the exact roles and mechanisms of SCD in modulating macrophage cholesterol efflux and atherosclerosis merit further investigation.