The field of cancer metabolism has undergone a renaissance in the last two decades with an emphasis on understanding dysregulated biochemical pathways in tumour development. However, translating this new metabolic knowledge for patient benefit has been very challenging for numerous reasons. Here, I will discuss over 20 years’ work depleting the amino acid arginine using pegargiminase (ADI-PEG20) as a novel antimetabolite therapy in a range of hard-to-treat cancers. Our recent phase 3 study in mesothelioma – under FDA review – has validated arginine deprivation for the treatment of cancer, and the goal now is to expand pegargiminase across multiple tumour indications.