Mammals that prey on venomous snakes include several opossums (Didelphidae), at least two hedgehogs (Erinaceidae), several mongooses (Herpestidae), several mustelids, and some skunks (Mephitidae). As a group, these taxa do not share any distinctive morphological traits. Instead, mammalian adaptations for ophiophagy seem to consist only in the ability to resist the toxic effects of snake venom. Molecular mechanisms of venom resistance (as indicated by biochemical research on opossums, mongooses, and hedgehogs) include toxin-neutralizing serum factors and adaptive changes in venom-targeted molecules. Of these, toxin-neutralizing serum factors have received the most research attention to date. All of the toxin-neutralizing serum proteins discovered so far in both opossums and mongooses are human α1B-glycoprotein homologs that inhibit either snake-venom metalloproteinases or phospholipase A2 myotoxins. By contrast, adaptive changes in venom-targeted molecules have received far less attention. The best-documented examples include amino-acid substitutions in mongoose nicotinic acetylcholine receptor that inhibit binding by α-neurotoxins, and amino-acid substitutions in opossum von Willebrand factor (vWF) that are hypothesized to weaken the bond between vWF and coagulopathic C-type lectins. Although multiple mechanisms of venom resistance are known from some species, the proteomic complexity of most snake venoms suggests that the evolved biochemical defences of ophiophagous mammals are likely to be far more numerous than currently recognized. Whereas most previous research in this field has been motivated by the potential for medical applications, venom resistance in ophiophagous mammals is a complex adaptation that merits attention from comparative biologists. Unfortunately, evolutionary inference is currently limited by ignorance about many relevant facts that can only be provided by future research.