Tetrodotoxin is a potent non-proteinaceous neurotoxin, which is commonly found in the marine environment. Synthesised by bacteria, tetrodotoxin has been isolated from the tissues of several genera including pufferfish, salamanders and octopus. Believed to provide a defensive function, the independent evolution of tetrodotoxin sequestration is poorly understood in most species. Two mechanisms of tetrodotoxin resistance have been identified to date, tetrodotoxin binding proteins in the circulatory system and mutations to voltage gated sodium channels, the binding target of tetrodotoxin with the former potentially succeeding the latter in evolutionary time. This review focuses on the evolution of tetrodotoxin acquisition, in particular how it may have occurred within the blue-ringed octopus genus (Hapalochlaena) and the subsequent impact on venom evolution.