Previous studies using stearoyl-CoA desaturase-1-deficient (SCD1-deficient) mice have shown that this enzyme plays an important role in many diseases of altered cellular metabolism including obesity, insulin resistance, and dyslipidemia. Although SCD1 activity is highest in lipogenic tissues such as the liver and adipose tissue, it is also present at lower levels in most tissues. To better understand the role of SCD1 in liver metabolism it is necessary to explore SCD1 deficiency in a more focused, tissue-specific manner. This commentary focuses on 2 recent studies published in the JCI that address this question using antisense oligonucleotide inhibition of SCD1. First, Jiang et al. have previously reported that long-term inhibition of SCD1 prevents the development of high-fat diet-induced obesity and hepatic steatosis. Second, Gutiérrez-Juárez et al. show in this issue that short-term inhibition of hepatic SCD1 is sufficient to prevent diet-induced hepatic insulin resistance, signifying an important role of hepatic SCD1 in liver insulin sensitivity (see related article beginning on page 1686).