Innate and adaptive immune responses are regulated by receptors that signal through immunoreceptor tyrosine-based activation motifs (ITAMs). The molecular basis of ITAM signaling has been extensively characterized and serves as a model for receptor-mediated signal transduction. Src family kinases typically phosphorylate ITAMs on dual tyrosines, which enable recruitment and activation of Syk family kinases through binding to dual SH2 domains on these kinases. Examples of ITAM-based signaling that do not conform precisely to the standard model are becoming increasingly common. ITAMs that suppress signaling under specific conditions and activate under others have been described, as have ITAM-like signaling mechanisms using nonstandard sequence motifs. Elucidating the diversity of ITAM-based signaling mechanisms will clarify how activating signals generated by ITAMs are tightly regulated and will open opportunities for specific therapeutic manipulation of ITAM-based signaling pathways.