Variation in venom components is inherent to multiple taxonomical levels of the Serpentes and can impact significantly upon the symptomatology of envenoming and the efficacy of antivenoms. Snake venom composition is thought to be subject to strong natural selection as a result of adaptations to specific diets, although no direct link at the molecular level has elucidated the evolutionary adaptations responsible for driving the optimisation of venom components to specific prey items. Venom gland cDNA libraries were constructed for three species of the genus Echis (E. pyramidum leakeyi, E. coloratus and E. carinatus sochureki) to complement the existing E. ocellatus transcriptome. Generated expressed sequence tags were clustered with a modified CLOBB algorithm, which was demonstrated to confer increases in the integrity of cluster formation and membership over the standard CLOBB2 algorithm. Comparative analyses of multiple Echis venom gland transcriptomes revealed the presence of snake venom metalloproteinases (SVMP), C-type lectins, phopholipases A2, serine proteases (SP), L-amino oxidases and growth factors throughout the genus. Putative novel venom proteins exhibiting similarity to lysosomal acid lipase/cholesteryl ester hydrolase and the metallopeptidases dipeptidyl peptidase III and neprilysin were also identified in the venom glands of individual species. Phylogenetic and gene tree parsimony analyses provide the first evidence of the genomic basis of snake venom adaptations as a response to alterations in diet, with SVMP and SP toxin families exhibiting diet- associated gene events that correlate strongly with a dietary shift to vertebrate feeding in E. coloratus. The diversification and retention of these coagulopathic and haemorrhagic toxins in E. coloratus correlates with significant differences in venom function in the form of in vivo haemorrhage, providing genetic and functional evidence of coevolution between diet and venom components. Selective evolutionary pressures were also determined to be capable of confounding the derivation of species relationships from toxin data, suggesting venom components should not be used as primary species identifiers. Finally, the E. ocellatus antivenom EchiTabG® was demonstrated to effectively neutralise the venom of African members of the genus Echis in spite of considerable intra-generic variation in venom components. These results strongly advocate the geographical expansion of EchiTabG® to treat Echis envenomations throughout the African continent.