Periodic episodes of low oxygen (hypoxia) and elevated CO2 (hypercapnia) accompanied by low pH occur naturally in estuarine environments. Under the influence of climate change, the geographic range and intensity of hypoxia and hypercapnic hypoxia are predicted to increase, potentially jeopardizing the survival of economically and ecologically important organisms that use estuaries as habitat and nursery grounds. In this review we synthesize data from published studies that evaluate the impact of hypoxia and hypercapnic hypoxia on the ability of crustaceans and bivalve molluscs to defend themselves against potential microbial pathogens. Available data indicate that hypoxia generally has suppressive effects on host immunity against bacterial pathogens as measured by in vitro and in vivo assays. Few studies have documented the effects of hypercapnic hypoxia on crustaceans or bivalve immune defense, with a range of outcomes suggesting that added CO2 might have additive, negative, or no interactions with the effects of hypoxia alone. This synthesis points to the need for more partial pressure of O2 × low pH factorial design experiments and recommends the development of new host∶pathogen challenge models incorporating natural transmission of a wide range of viruses, bacteria, and parasites, along with novel in vivo tracking systems that better quantify how pathogens interact with their hosts in real time under laboratory and field conditions.