Gout results from an innate immune response to monosodium urate (MSU) crystals deposited in joints and soft tissues. Progression through three key stages is required: elevated serum urate levels (hyperuricemia), formation of MSU crystals and the subsequent inflammatory response to the crystals. Progression is not inevitable, with susceptibility regulated by inherited genetic variants and environmental and intrinsic exposures. Here, we review the current state of knowledge, largely generated by genome-wide association studies, of the genetic basis of hyperuricemia and the immune response to MSU crystals. These findings emphasize the importance of uric acid excretory molecules in determining hyperuricemia. Less is known about the genetic basis of the immune response, although current findings highlight the importance of the NLRP3 inflammasome. We also outline non-additive interactions that occur between environmental and intrinsic factors, and genetic variants.