Tasmanian Devil Facial Tumour Disease (DFTD) is an aggressive clonally transmissible cancer in Tasmanian devils, and the core cause driving the decline in their population. There are currently no effective treatments reflecting a lack of understanding of the DFTD biology. Notably, in human cancers, genome wide CRISPR screens have helped unravel disease mechanisms and guide the development of new therapies. Since no equivalent tools exist for the Tasmanian devil species, we engineered a genome-wide CRISPR KO library capable of interrogating DFTD biology. Using this approach, we screened for essential cancer genes and identified hundreds of genes required for DFTD tumour cell survival. Of these we ranked the top genes and individually validated 16 targets. We then identified enriched biological pathways essential for this cancer to detect possible therapeutic targets. Importantly, our data highlighted new drugs that can kill DFTD cells which we validated using 2D and 3D cultures. Overall, we describe the first use of whole genome CRISPR screening of the Tasmanian devil genome, and in the context of DFTD, we describe a new therapeutic strategy to help this endangered species.