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Abstract Many lizard species face extinction due to worldwide climate change. The Guatemalan Beaded Lizard, Heloderma charlesbogerti, is a member of the Family Helodermatidae that may be particularly imperiled; fewer than 600 mature individuals are believed to persist in the wild. In addition, H. charlesbogerti lizards are phenotypically remarkable. They are large in size, charismatically patterned, and possess a venomous bite. Here, we report the draft genome of the Guatemalan Beaded Lizard using DNA from a wild-caught individual. The assembled genome totals 2.31 Gb in length, similar in size to the genomes of related species. Single-copy orthologs were used to produce a novel molecular phylogeny, revealing that the Guatemalan Beaded Lizard falls into a clade with the Asian Glass Lizard (Anguidae) and in close association with the Komodo Dragon (Varanidae) and the Chinese Crocodile Lizard (Shinisauridae). In addition, we identified 31,411 protein-coding genes within the genome. Of the genes identified, we found 504 that evolved with a differential constraint on the branch leading to the Guatemalan Beaded Lizard. Lastly, we identified a decline in the effective population size of the Guatemalan Beaded Lizard approximately 400,000 years ago, followed by a stabilization before starting to dwindle again 60,000 years ago. The results presented here provide important information regarding a highly endangered, venomous reptile that can be used in future conservation, functional genetic, and phylogenetic analyses.