Since the first association between HLA and diseases of native kidneys was described almost 50 years ago, technological and conceptual advances in HLA biology and typing, together with better case ascertainment, have led to an improved understanding of HLA associations with a variety of renal diseases. A substantial body of evidence now supports the existence of HLA genetic associations in the field of renal disease beyond the role of HLA in allogeneic responses in transplant recipients. Allomorphs of HLA have emerged as important risk factors in most immune-mediated renal diseases, which, together with other genetic and environmental factors, lead to loss of tolerance and autoimmune-mediated renal inflammation. HLA associations have also been described for renal diseases that are less traditionally seen as autoimmune or immune-mediated. Here, we review essential concepts in HLA biology and the association of HLA with diseases of the native kidneys, and describe the current understanding of the epistatic and mechanistic bases of HLA-associated kidney disease. Greater understanding of the relationship between HLA and kidney function has the potential not only to further the understanding of immune renal disease at a fundamental level but also to lead to the development and application of more effective, specific and less toxic therapies for kidney diseases.