A major unresolved paradox in immunology remains: how do we avoid harm, despite the abundant opportunities for induction of immune responses against self-proteins? Here, Mohammad Ibrahim, Benjamin Chain and David Katz extend Janeway's proposed explanation, arguing that adaptive immune responses are initiated not only by conserved microbial products, but also by microenvironmental tissue injury. They suggest that the key step is local dendritic cell activation, followed by upregulation of T-cell costimulatory molecules on these cells, and migration, leading to antigen presentation.