With the increasing interest in developing gene therapies for rare diseases, it is easy to overlook that there are numerous rare lysosomal storage diseases (LSDs) with treatments that have been approved by regulatory agencies in the United States and Europe. These primarily consist of enzyme replacement therapies (ERTs)—recombinant human proteins that are delivered for the life of the patient through different routes and may offer distinct safety and distribution advantages over gene therapies. The research and development of ERT is a lengthy and expensive process, usually performed in academic laboratories before transfer to pharmaceutical companies and hence a process ripe for disruption. To realize fully the considerable scientific and investment potential for ERT, 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.