Rheumatic diseases are prevalent in Native American adults at rates five to seven times higher than those seen in the Caucasian population. Little, however, has been published concerning rheumatic diseases in Native American children. The authors' work in Oklahoma and with tribes on the northern Great Plains demonstrates high rates of childhood-onset rheumatic disease in this population. Familial disease is common, and large, multiplex kindreds showing strong founder effects are likely found within specific Native American tribes. However, a deeper understanding of the genetic and environmental triggers of rheumatic disease in Native Americans will require a respect and appreciation for the specific and unique cultural and social issues that impinge on research with Native Americans and other indigenous people.