The past decade has witnessed several large SMA drug development projects coordinated by the National Institute of Neurological Disorders and Stroke, private foundations, and the pharmaceutical and biotechnology industries. These projects have focused on developing cell-based, high-throughput assays to screen for candidate small molecules that can increase SMN protein levels. Compounds that increase SMN levels in these assays have been tested in SMA animal models. Through this approach, a diverse set of compounds has been identified that include histone deacetylase inhibitors, aminoglycosides, and quinazoline derivatives. Histone deacetylase inhibitors such as valproic acid, sodium butyrate, phenylbutyrate, and trichstatin A activate the SMN2 promoter, resulting in increased full-length SMN protein. Despite favorable results in mouse models, clinical trials with several of these agents, most notably phenylbutyrate, valproic acid, and hydroxyurea have been disappointing, with no substantial clinical benefit demonstrated. Despite multiple issues related to dosing, duration of therapy, and timing of therapy (ie, when in the course of the disease therapy is instituted), trials with several of these agents are currently under way.