Today's most successful class of biologics targets the inflammatory cytokine tumor necrosis factor in autoimmune diseases including rheumatoid arthritis, psoriasis and Crohn's. With five anti-TNF biologics now on the market, attention has turned toward novel strategies to improve the safety and efficacy of next-generation TNF inhibitors. Beyond TNF, drugs are under development that modulate many other ligands and receptors of the TNF superfamily. Biologics targeting at least 16 of the approximately 22 known ligand-receptor pairs are now in clinical development for autoimmune diseases, cancers and osteoporosis. A deeper understanding of intracellular signaling has also facilitated small-molecule interventions, opening the door to oral therapies. This report summarizes recent developments in this highly druggable superfamily, including highlights of the latest international TNF conference.