SCD1 is a novel target for the treatment of dyslipidemia, obesity, and other symptoms of metabolic syndrome. Extensive target validation has been obtained using SCD1-deficient mice, anti-sense oligonucleotide and RNA interference-mediated knockdown of SCD1, and has supported a controlling role for SCD1 in regulation of lipid biosynthesis and energy expenditure. In this review, the recent advances in small-molecule SCD1 inhibitors will be summarized. The pharmacological and adverse effects of SCD1 inhibitors in relevant rodent models will also be reviewed. The future prospect of SCD1 inhibition in the treatment of metabolic diseases will be discussed.