Statin therapy reduces cardiovascular events in patients with, or at risk of, atherosclerotic cardiovascular disease. However, statins are underutilized in patients for whom they are indicated and are frequently discontinued. Discontinuation may be the result of statin-associated muscle symptoms (SAMS), which encompass a broad spectrum of clinical phenotypes from myalgia to severe myopathy. As with many adverse drug reactions (ADRs), inter-individual variability in susceptibility to SAMS is due, at least in part, to differences in host genetics. The genetic basis for SAMS has been investigated in candidate gene studies, genome-wide association studies, and, more recently, studies of multi-omic networks, including at the transcriptome level. In this article, we provide a systematic review of the pharmacogenetic basis of SAMS, focusing on how an understanding of the genetic and molecular determinants of SAMS can be considered in a personalized approach to reduce the incidence of this ADR, optimize statin adherence, and reduce the risk for cardiovascular events.