Cyclooxygenases (COX-1 and COX-2) are key enzymes in several physiopathological processes. Many adverse drugs reactions to NSAIDs are attributable to COX-inhibition. The genes coding for these enzymes (PTGS1 and PTGS2) are highly variable, and variations in these genes may underlie the risk of developing, or the clinical evolution of, several diseases and adverse drug reactions. We analyze major variations in the PTGS1 and PTGS2 genes, allele frequencies, functional consequences and population genetics. The most salient clinical associations of PTGS gene variations are related to colorectal cancer and stroke. In many studies, the SNPs interact with NSAIDs use, dietary or environmental factors. We provide an up-to-date catalog of PTGS clinical associations based on case–control studies and genome-wide association studies, and future research suggestions.