SLE is a debilitating autoimmune disease with limited treatment options. Features of SLE include chronic T and B cell activation and HDL dysfunction. Studies show that SLE patient HDL lack cardio-protective characteristics and are associated with signaling and protein expression changes, suggesting differential regulatory functions of SLE HDL. We recently reported that HDL transfers functional microRNAs (miRNA) to cells in a scavenger receptor BI (SR-Bl)-dependent manner. SR-BI null mice develop a lupus-like autoimmune disorder including T and B cell activation and cell proliferation, pointing to a role for HDL-mediated miRNA transfer in maintaining immune homeostasis. Lending further support are preliminary data indicating that monocytes, macrophages, and T cells export miRNAs to HDL. Taken together, this suggests that HDL-mediated communication between disparate cell types may be altered in SLE. Therefore, we hypothesize that dysregulation of HDL-mediated miRNA transfer between macrophages, T cells and B cells is an important molecular mechanism underlying SLE disease pathogenesis. Understanding this mechanism will result in alteration of the current paradigm of cell-to-cell communication in autoimmune disorders and allow for identification of novel SLE drug targets.