Lysosomal storage diseases (LSDs), as a group, are among the most common inherited diseases affecting children. The primary defect is typically a genetic deficiency of one of the lysosomal enzymes, often causing accumulation of undegraded substrates within the lysosome. This accumulation causes numerous secondary effects that contribute to the disease phenotype. Viral-mediated gene therapy (GT) can supply a persistent source of the deficient enzyme. However, with some notable exceptions, GT has been only modestly successful as a single approach. Recently, various therapies have been combined in order to more effectively target the diverse pathogenic mechanisms at work in LSDs. One strategy that has shown promise involves providing a persistent source of the deficient enzyme (GT, stem cell transplantation) while targeting a secondary consequence of disease with a more transient approach (substrate reduction, anti-inflammatories, pharmacological mimetic, etc.). This general strategy has resulted in both additive and synergistic effects. Interestingly, some therapeutic approaches by themselves provide essentially no clinical benefit but contribute greatly to the overall efficacy when used in combination with other treatments. Unfortunately, no therapeutic combination is universally effective. This adds to the difficulty in predicting and identifying combinations that will be most effective for individual LSDs. A better understanding of both pathogenic and therapeutic mechanisms is necessary in order to identify potentially successful combinations. While a single treatment would be ideal, the complex nature of these diseases may unavoidably limit the efficacy of single therapies. In order to more successfully treat LSDs, a shift in focus towards a combination therapy may be necessary.