With the introduction of potent combination antiretroviral therapy (cART) into clinical practice, HIV-infected patients have garnered much benefit. However, kidney disease continues to be a potential complication in this group. Whereas HIV-associated nephropathy (HIVAN) was the major renal complication prior to cART, co-morbid diseases and adverse renal effects of various drugs, in particular cART, now complicate the landscape. Clinicians now must differentiate HIVAN from cART nephrotoxicity. While sometimes this is easy and relatively straightforward, often the clinician faces a difficult challenge distinguishing these two etiologies of kidney disease. This review will discuss HIVAN and cART-related kidney disease and review the clinical and laboratory data that may be useful in differentiating these processes. Often, however, kidney biopsy may be required to differentiate HIVAN from cART nephrotoxicity as well as other kidney lesions associated with concurrent co-morbidities, both infectious and non-infectious.