Rheumatic diseases follow a characteristic anatomical pattern of joint and organ involvement. This Review explores three interconnected mechanisms that might be involved in the predilection of specific joints for developing specific forms of arthritis: site-specific local cell types that drive disease; systemic triggers that affect local cell types; and site-specific exogenous factors, such as focal mechanical stress, that activate cells locally. The embryonic development of limbs and joints is also relevant to the propensity of certain joints to develop arthritis. Additionally, location-specific homeostasis and disease occurs in skin and blood vessels, thereby extending the concept of site-specificity in human diseases beyond rheumatology. Acknowledging the importance of site-specific parameters increases the complexity of current disease paradigms and brings us closer to understanding why particular disease processes manifest at a particular location.