Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders, which lack an enzyme corresponding to the specific type of MPS. Enzyme replacement therapy (ERT) has been the standard therapeutic option for some types of MPS because of the ability to start immediate treatment with feasibility and safety and to improve prognosis. There are several disadvantages for current ERT, such as limited impact to the brain and avascular cartilage, weekly or biweekly infusions lasting 4-5 h, the immune response against the infused enzyme, a short half-life, and the high cost. Clinical studies of ERT have shown limited efficacy in preventing or resolving progression in neurological, cardiovascular, and skeletal diseases. One focus is to penetrate the avascular cartilage area to at least stabilize, if not reverse, musculoskeletal diseases. Although early intervention in some types of MPS has shown improvements in the severity of skeletal dysplasia and stunted growth, this limits the desired effect of ameliorating musculoskeletal disease progression to young MPS patients. Novel ERT strategies are under development to reach the brain: (1) utilizing a fusion protein with monoclonal antibody to target a receptor on the BBB, (2) using a protein complex from plant lectin, glycan, or insulin-like growth factor 2, and (3) direct infusion across the BBB. As for MPS IVA and VI, bone-targeting ERT will be an alternative to improve therapeutic efficacy in bone and cartilage. This review summarizes the effect and limitations on current ERT for MPS and describes the new technology to overcome the obstacles of conventional ERT.