While the PME are arguably the severest epilepsies and neurological disorders, the vast majority are monogenic. Additionally, many affect straightforward biochemical pathways. Finally, by definition, they occur in previously healthy and well‐developed brains. As such, their therapies should be easier than in complex, albeit often less severe, neurological developmental disorders where the complex, poorly understood, and extremely difficult‐to‐correct, neural network of the brain is affected. This last article reviews the latest cutting edge technologies in monogenic disease therapy, with some examples provided applicable to a number of disease. It aims to give a sense of where we are and how much closer we are, to the goal of making an actual organic difference.