Many entities affect specifically the tubulointerstitium, most often sparing the glomeruli and vessels, but exact subclassification is difficult because the histologic findings may have overlapping features. Frequently biopsies are performed shortly after symptoms manifest (in the acute phase). There is controversy in the terminology of chronic lesions; for example the term chronic pyelonephritis, particularly in the pediatric population, has fallen out of favor, replaced by other terms such as reflux nephropathy. However, careful examination and clinicopathologic correlation helps to pinpoint the cause and guide appropriate patient management. In this chapter, the focus is on the histopathology of acquired and hereditary tubulointerstitial diseases in native kidneys.