Venom is a key innovation underlying the evolution of advanced snakes (Caenophidia). Despite this, very little is known about venom system structural diversification, toxin recruitment event timings or toxin molecular evolution. A multidisciplinary approach was employed examine the diversification of the venom system and associated toxins across the full-range of the ~100 million year old advanced snake clade, with a particular emphasis upon families that have not secondarily evolved front-fanged venom system (~80% of the 2500 species). Analysis of cDNA libraries revealed complex venom transcriptomes containing multiple toxin types including three finger toxins, cobra venom factor, CRISP, hyaluronidase, kallikrein, kunitz, lectin, matrix metalloprotease, phospholipase A2, snake venom metalloprotease/ADAM and waprin. High levels of sequence diversity were observed, including mutations in structural and functional residues, changes in cysteine spacing, and major deletions/truncations. Morphological analysis comprising gross dissection, histology and magnetic resonance imaging also demonstrated extensive modification of the venom system architecture in non-front-fanged snakes, in contrast to the conserved structure of the venom system within the independently evolved front-fanged elapid or viperid snakes. Further, a reduction in the size and complexity of the venom system was observed in species in which constriction has been secondarily evolved as the preferred method of prey capture or dietary preference has switched from live-prey to eggs or to slugs/snails. Investigation of the timing of toxin recruitment events across the entire advanced snake radiation indicates that the evolution of advanced venom systems in three front-fanged lineages are associated with recruitment of new toxin types or explosive diversification of existing toxin types. These results support the role of venom as a key evolutionary innovation in the diversification of advanced snakes and identify a potential role for non-front-fanged venom toxins as a rich source for lead compounds for drug design and development.