Despite the opioid epidemic, up to 86% of patients experience moderate to severe pain after major surgery. Although several factors influence the amount of pain patients experience postoperatively, studies have identified genetic variations that influence pain perception and response to pain medications. The purpose of this article is to examine evidence of the genetic differences that affect patients' responses to medications frequently used in postoperative pain management. Genes of interest associated with postoperative pain management include the opioid μ1 receptor (OPRM1), cytochrome P450 (CYP) enzymes, catechol O-methyl transferase (COMT) enzyme, and adenosine triphosphate-binding cascade (ABCB1) transporter. There is moderate evidence linking the OPRM1 sequence variation and response to morphine in the postoperative period. Besides activity at the OPRM1 receptor, analgesic efficacy and adverse effects of pain medications also depend on their rate of metabolism by CYP enzymes. CYP2D6 enzymes metabolize codeine and tramadol. Codeine and tramadol are not recommended in CYP2D6 poor metabolizers and ultrarapid metabolizers and are contraindicated in children and breastfeeding mothers. Similarly, caution must be exercised when using nonsteroidal anti-inflammatory drugs in CYP2C9 intermediate metabolizers and poor metabolizers. Large-scale studies are needed to develop genotype-guided therapeutic guidelines for most medications used in postoperative pain management.