Predator–prey interactions have long served as models for the investigation of adaptation and fitness in natural environments. Anti-predator defences such as mimicry and camouflage provide some of the best examples of evolution. Predators, in turn, have evolved sensory systems, cognitive abilities and physiological resistance to prey defences. In contrast to prey defences which have been reviewed extensively, the evolution of predator counter-strategies has received less attention. To gain a comprehensive view of how prey defences can influence the evolution of predator counter-strategies, it is essential to investigate how and when selection can operate. In this review we evaluate how predators overcome prey defences during (i) encounter, (ii) detection, (iii) identification, (iv) approach, (v) subjugation, and (vi) consumption. We focus on prey that are protected by cardiotonic steroids (CTS)—defensive compounds that are found in a wide range of taxa, and that have a specific physiological target. In this system, coevolution is well characterized between specialist insect herbivores and their host plants but evidence for coevolution between CTS-defended prey and their predators has received less attention. Using the predation sequence framework, we organize 574 studies reporting predators overcoming CTS defences, integrate these counter-strategies across biological levels of organization, and discuss the costs and benefits of attacking CTS-defended prey. We show that distinct lineages of predators have evolved dissecting behaviour, changes in perception of risk and of taste perception, and target-site insensitivity. We draw attention to biochemical, hormonal and microbiological strategies that have yet to be investigated as predator counter-adaptations to CTS defences. We show that the predation sequence framework will be useful for organizing future studies of chemically mediated systems and coevolution.