Substance abuse (including illicit and prescription drugs) has become a significant public health and economic burden. Acute and chronic substance use often leads to a pathologic pattern of behaviors as well as physiologic manifestations, such as tolerance and withdrawal, collectively called substance use disorders (SUDs). Clinical and animal studies have demonstrated that SUDs are heritable in both humans and rodents. The exact molecular mechanism(s), however, is mostly unclear. Long noncoding RNAs (lncRNAs) have emerged as pivotal epigenetic regulators of gene expression in various human diseases, including SUDs. This chapter summarizes current findings and thoughts on the dysregulation as well as the role of lncRNAs in the context of the use of substances, such as morphine, cocaine, methamphetamine, alcohol, etc. The potential applications of lncRNAs in SUDs will also be discussed in this chapter.