ABSTRACT. Osteoarthritis (OA) is a complex disease that affects the whole joint, with multiple biological and environmental factors contributing to its development. The heritable component for primary OA accounts for ~50% of susceptibility. So far, candidate gene studies and genome-wide association scans have established 18 OA-associated loci. These findings account for 11% of the heritability, explaining a rather small fraction of the genetic component. To further unravel the genetic architecture of OA, the field needs to facilitate more precise phenotypic definitions, high genome coverage, and large sample metaanalyses, expecting the identification of rare and low frequency variants with potentially higher penetrance, and more accurate methods for calculating phenotype-genotype correlation. Expression analysis, epigenetics, and investigation of interactions can also help clarify the implicated transcriptional regulatory pathways and provide insights into further novel pathogenic OA mechanisms leading to diagnostic biomarker identification and new, more focused therapeutic disease approaches