In this edition of ‘Then and now’ the initial studies by J.C. Pickup and colleagues supporting the hypothesis that type 2 diabetes is caused by activated innate immunity, published in Diabetologia in 1997 (40:1286–1292), are discussed. These initial findings led to research that has uncovered links between insulin resistance, obesity, circulating immune markers, immunogenetic susceptibility, macrophage function and chronic infection. Genetic variations leading to the altered production or function of circulating innate immune proteins, cellular pattern recognition receptors and inflammatory cytokines are linked to obesity, insulin resistance and type 2 diabetes. Components of the innate immune system in the muscle, bone, liver and adipose tissue, as well as macrophages, have been revealed to play a role in systemic insulin action. Evolutionary pressures, such as acute infections at the population level (pandemics) and chronic low exposure to environmental products or infectious agents, may have contributed to increased susceptibility and to the current increase in the prevalence of insulin resistance and type 2 diabetes.