Most often, disease is considered the outcome of a collision between a pathogenic agent and a susceptible host. Cellular and tissue degradation are pathognomonic of microbial proliferation—but the aetiology of non-communicable disease or stress is difficult to outline and has received much less coverage. Non-communicable diseases (NCDs) are those that are not transmissible between hosts. Secondary and opportunistic infections linked to a primary abiotic disruptor can be misdiagnosed as the causative agent. Moreover, stress from fluctuating environmental parameters and pollutants, and injury from predators/conspecifics can compromise the health of an invertebrate, paving the way for opportunistic infections. In addition to pathogens and parasites, terrestrial and aquatic invertebrates must also contend with a myriad of xenobiotic contaminants, such as hydrocarbons, heavy metals, pesticides, plastics, pharmaceuticals, and toxins. These contaminants can be found in the environments they reside in (air, water, and soil), the foods they eat due to bioaccumulation, and across trophic levels due to biomagnification. In this unique chapter, invertebrate defences toward ‘sterile’ diseases (e.g. neoplasia) and stress are discussed, with a particular emphasis placed on the ‘chemical defensome’, which is made up of REDOX enzymes, detoxicants, antioxidants, ATP-dependent efflux transporters, and the factors that regulate and maintain the detoxification machinery.