The MHC class II molecules have been recognized as signaling receptors for more than a decade, and recent work has revealed the importance of their signaling for the immune response. Today, we know that the function of MHC class II molecules on antigen-presenting cells (APCs) is not limited to their role as antigen-presenting structures; they are flexible receptors that, by triggering a variety of signaling pathways, can regulate APC activities from proliferation and maturation to apoptosis. Recent advances have provided insights into how these molecules might accommodate such regulation.