Basic calcium phosphate, calcium pyrophosphate dihydrate, and monosodium urate crystals are the most common types of crystals associated with human disease. Although there is a well-established association between these crystals and various forms of joint disease, recent evidence points to an association of basic calcium phosphate crystals with breast cancer and atherosclerosis. Crystal-induced tissue damage is affected by degradative proteases, cytokines, chemokines, and prostanoids produced by cells stimulated by crystals. In the case of basic calcium phosphate and calcium pyrophosphate dihydrate crystals, these responses are augmented by the cellular proliferation that results from their induction of mitogenesis. The understanding of the molecular mechanisms involved in generating these pathologic effects has been significantly advanced in recent years. Such advances are essential to the ongoing search for more effective therapies for crystal-associated diseases.