Integrins are αβ heterodimeric receptors that connect the extracellular environment with intracellular signaling events. Integrins are important for normal development and function, but are also involved in the pathogenesis of diseases including cancer, autoimmunity and heart disease. We will review the present data on a family of integrins, the collagen receptors that include the α1β1, α2β1, α10β1 and αα11β1 integrins. We will describe the knowledge gained from genetic deletion of each integrin in animal models. Mice lacking any single collagen receptor display no overt defect. However, studies using the α1β1 and α2β1 integrin-deficient mice indicate that these receptors play an important role in innate immunity, inflammation and autoimmunity. Finally, we will elucidate the interesting and sometimes overlapping roles for α1β1 and α2β1 integrins in disease and will propose potential stategies to therapeutically target these receptors to alleviate or treat disease.