Abstract GASPIDs (granule associated serine protease of immune defence) are a family of serine proteases intimately involved with the function of the vertebrate immune system. With the availability of a large and growing set of assembled genomes, we undertook an evolutionary analysis to plot the development of this protein family from a single precursor to the modern mammalian cohort of 12 genes, in an attempt to define and systematically classify subgroups or clades within this family, which are implied by the conventional gene designations. We identified a primordial GASPID gene as either GzmA or GzmK in cartilaginous fish and reconstructed an evolutionary path through to humans. Apart from historic value, the current sub-designations (granzymes, mast cell proteases and neutrophil serine proteases) serve no useful purpose and are increasingly misleading. We therefore used our phylogenetic and point mutation analyses to separate GASPIDs into three clades. These could form the basis of a simple nomenclature that allows effective classification of GASPIDs without implying functional roles.