Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by a breakdown in immune tolerance leading to the development of auto-reactive lymphocytes and autoantibodies. Recent findings have provided new insight on the role of the signaling lymphocytic activation molecule family (SLAMF) receptors, a group of nine co-regulatory molecules involved in the activation of hematopoietic cells, and their downstream protein SLAM-associated protein (SAP), into the pathogenesis of SLE. This review summarizes the current knowledge on SLAMF in human SLE immunopathogenesis, and the importance of SLAMF molecules as new therapeutic targets.