The inoceramid bivalves were dominant constituents of marine, epifaunal communities throughout the Late Mesozoic. They experienced a rapid decline in the Early Maastrichtian and virtually all taxa disappeared 1.5 Myr prior to the Cretaceous-Tertiary (K-T) boundary. The ultimate cause for their demise is still controversial. This study evaluates the role predation, parasitism and/or disease played in the evolution and extinction of Early Maastrichtian inoceramids from the Western Interior Seaway of North America (WIS). Escalation - the ‘evolutionary arms race’ between predators and prey - is said to be one of the most influential selective agents in evolution. Evidence of predation, parasitism, and disease in inoceramids is virtually undocumented prior to the Turonian. However, populations of inoceramids from the Late Cretaceous Pierre Shale show a marked increase in the number of individuals in which evidence for attempted predation and/or parasitism is preserved. The percentage of predation and/or parasitism steadily increases between the Baculites baculus and the B. grandis ammonite biozones (uppermost Campanian through Lower Maastrichtian) from 2.6% to values as high as 44.6%. The dramatic increase in shell deformities among inoceramids corresponds to a rapid radiation of shell-crushing brachyuran crabs and may be related to their activity. The introduction of new, efficient predators, such as brachyuran crabs, combined with parasitism and disease could have stressed inoceramid populations. Thus, they may have been more susceptible to environmental perturbations than under normal ‘background’ conditions. The disappearance of the inoceramids, at least from the WIS, may be one of the few cases where virtually an entire family lost the ‘evolutionary arms race’.