Signals emanating from many cell-surface receptors and environmental cues converge on mitogen-activated protein kinases (MAPKs), which in turn phosphorylate and activate various transcription factors and other molecular effectors. Members of the p38 MAPK family, which respond to pro-inflammatory cytokines and cellular stresses, are typically activated by serial phosphorylation and activation of upstream kinases (the MAPK cascade). In this Review, I highlight the recent studies that indicate that p38-subfamily members can also be activated by non-canonical mechanisms, at least one of which seems to have an important role in antigen-receptor-activated T cells. These alternative pathways might have particular relevance for cells that participate in immune and inflammatory responses.