The signaling lymphocytic activation molecule (SLAM) and SLAM-associated protein (SAP) families have key roles in normal immunity. They have also been implicated in diseases such as immunodeficiencies and auto-immunity. However, recent findings raise issues requiring examination in future investigations of these molecules. First, Slam-related genes have peculiar features that need to be considered when generating mice lacking SLAM family receptors. Second, there are outstanding questions concerning the functions and mechanisms of action of the SLAM and SAP families. Among these is the possibility that certain properties of these families are not conserved between humans and mice, a controversy about the role of SAP in B cells, gaps in our understanding of the mechanisms by which SAP and Ewing's sarcoma-related transcript (EAT)-2 mediate their signals, and the notion that SLAM family receptors might regulate components of normal immunity in the absence of SAP-related adaptors. We address these issues and discuss the recent progress in this research area.