Recently, genome‐wide association studies have identified the major histocompatibility complex class I protein HLA‐C as an important molecule that affects HIV disease progression. The association between HLA‐C and HIV disease outcome was originally determined through a single nucleotide polymorphism (SNP) 35 kb upstream of the HLA‐C locus. More recent work has focused on elucidating the functional significance of the ‐35 SNP, and several groups now have demonstrated HLA‐C surface expression to be a key element in control of HIV viral load, with higher surface expression associating with slower disease progression. Most recently, control of HLA‐C surface expression has been correlated with the presence of microRNA binding sites that affect HLA‐C expression and control of HIV disease. This review highlights these results and explores the ways in which HLA‐C surface expression could affect immune system function in the setting of HIV disease.