Exposure to infectious agents elicits defense mechanisms that necessitate a timely immune response. The immediate delivery of essential cues for immune activation is provided, in part, by proteolytic processing. A large repertoire of molecules orchestrates the activation, migration, and effector function of immune cells. The diversity of this repertoire matches well with the broad array of substrates that can be cleaved by proteinases, and many of these substrates are proving to be essential for proper immune-cell function. Here, we discuss how two specific classes of metal-dependent proteinases, the matrix metalloproteinases and the disintegrin metalloproteinases, have consequences well beyond classical cell-matrix and cell-cell interactions and motility, and we review their roles in immune-cell maturation, clonal expansion, and cytotoxic functions.