Rett syndrome (RTT) is a rare neurogenetic disorder caused by pathogenic variants of the Methyl CpG binding protein 2 () gene. The RTT is characterized by apparent normal early development followed by regression of communicative and fine motor skills. Comorbidities include epilepsy, severe cognitive impairment, and autonomic and motor dysfunction. Despite almost 60 clinical trials and the promise of a gene therapy, no cure has yet emerged with treatment remaining symptomatic. Advances in understanding RTT has provided insight into the complexity and exquisite control of expression, where loss of expression leads to RTT and overexpression leads to duplication syndrome. Therapy development requires regulated expression that matches the spatiotemporal endogenous expression of in the brain. Gene editing has revolutionized gene therapy and promises an exciting strategy for many incurable monogenic disorders, including RTT, by editing the native locus and retaining endogenous gene expression. Here, we review the literature on the currently available editing technologies and discuss their limitations and applicability to the treatment of RTT.