We investigated population responses of Mysis to ecosystem changes induced by invasion of dreissenids and predatory cladocerans, Cercopagis and Bythotrephes. Lake productivity declined as dreissenids invaded the offshore region. Whole-lake mysid biomass was compared before (early 1990s) and after (2002–2007) the invasion period; it declined 40%–45%. Abundance of young mysids and presence of a summer cohort increased with summer, epilmnetic, nighttime zooplankton biomass (i.e., food biomass index). Cercopagis + Bythotrephes biomass was negatively correlated with this index, implicating them in the mysid decline. Eggs per gravid female increased with autumn, total-water-column zooplankton biomass, reflecting the greater use of hypolimnetic waters by adults. Reproductive success was below replacement during the period 2002–2005. First-year mysid growth rate was maintained while population abundance declined, suggesting selection for individuals that feed effectively at low food concentrations. Mortality rates in the first and second years were dependent on cohort density, indicating that competition for food limited abundance in the first 2 years. Fish predation indices (smelt and alewife combined) were correlated positively with mortality rates and negatively with abundance in the third year. Thus, mysids cannot support as many fish in invaded compared with non-invaded lakes. They may also not be a stable food resource; unusual cohort losses occurred in some years.