Endogenous opioids acting at mu-opioid receptors mediate many biological functions. Pharmacological intervention at these receptors has greatly aided in the treatment of acute and chronic pain, in addition to other uses. However, the development of tolerance and dependence has made it difficult to adequately prescribe these therapeutics. A common single nucleotide polymorphism (SNP), A118G, in the mu-opioid receptor gene can affect opioid function and, consequently, has been suggested to contribute to individual variability in pain management and drug addiction. Investigation into the role of A118G in human disease and treatment response has generated a large number of association studies across various disease states as well as physiological responses. However, characterizing the functional consequences of this SNP and establishing if it causes or contributes to disease phenotypes have been significant challenges. In this manuscript, we will review a number of association studies as well as investigations of the functional impact of this gene variant. In addition, we will describe a novel mouse model that was generated to recapitulate this SNP in mice. Evaluation of models that incorporate known human genetic variants into a tractable system, like the mouse, will facilitate the understanding of discrete contributions of SNPs to human disease.