The apparent efficacy of B-cell depletion in autoimmune diseases has increased interest in targeting B cells. One goal of next generation therapies is to develop treatments that block B-cell activation and preserve resting nonautoimmune cells that maintain B cell memory. To do so, one needs to understand how B cells are activated and what receptors and intracellular signaling pathways regulate this process. This paper will summarize B-cell activation pathways and illustrate how these are being targeted in the development of new treatments for rheumatoid arthritis.