With the increasing interest in developing gene therapies for rare diseases, it is easy to overlook that there are numerous rare lysosomal storage diseases (LSD) with treatments that have been approved by regulatory agencies in the United States and Europe. These primarily consist of enzyme replacement therapies (ERT), which are recombinant human proteins that are delivered for the life of the patient via different routes and may have distinct safety and distribution advantages over gene therapies. The research and development of ERT is a lengthy and expensive process, which is usually performed in academic laboratories before transfer to pharmaceutical companies and is hence a process ripe for disruption. There may still be considerable scientific and investment potential for ERT, however we need to develop a pipeline of proteins analogous to what has been created in some open science efforts as well as apply technologies to decrease manufacturing costs. In this Perspective, we illustrate the opportunity to fill the rare LSD treatment gap with ERTs while gene therapies are in development for these life-shortening diseases.