The chromatin-associated cellular proteins LEDGF/p75 and LEDGF/p52 have been implicated in transcriptional regulation, cell survival and autoimmunity. LEDGF/p75 also appears to act as a chromatin-docking factor or receptor for HIV-1 and other lentiviruses and to play a role in leukemogenesis. For both the viral and cellular roles of this protein, a key feature is its ability to act as a molecular adaptor and tether proteins to the chromatin fiber. This chapter reviews the emerging roles of LEDGF/p75 and LEDGF/p52 in diverse cellular processes and disease states.