Lysosomal storage diseases (LSDs) are rare genetic conditions that frequently result in deficient or defective lysosomal enzymes which cause substrate accumulation, multiorgan pathology, clinical morbidity, and early mortality. Clinical and biochemical improvements observed with enzyme replacement therapy (ERT) in both clinical studies and real-world experience have validated the benefit of enzyme replacement for several LSDs. While this therapy offers significant improvements for patients, ERT has its limitations. Exogenously infused enzymes have short half-lives, are rapidly cleared, and fail to penetrate the blood-brain barrier. Furthermore, unmet needs persist. These can range from absent to ineffective therapies for some LSDs, suboptimal response and/or continued disease progression despite available therapies, in others, and ongoing treatment burden in yet others. Ex-vivo, lentiviral vector mediated gene therapy (LVGT) is a platform with over 10 years of promising efficacy and safety observations involving more than 200 participants in rare-disease clinical trials. In contrast to ERT, autologous hematopoietic stem cells that have been returned following ex-vivo LVGT have the potential to produce progeny that constitutively express sustained levels of endogenous, functional enzyme. Given these observations, the potential benefit of ex-vivo LVGT for the durable treatment of several LSDs, including Fabry disease and Gaucher disease will be discussed.