Treatment of pathologic muscle overactivity associated with upper motor neuron syndrome can be multifaceted. One of the initial decisions to be made when formulating an overarching treatment plan is selecting a combination of strategies that is most applicable. Strategies may include physical interventions, such as stretching or splinting modalities, or surgery, whereas pharmacotherapeutic strategies encompass oral/systemic medications as well as agents, such as toxins and alcohols, used for focal chemodenervation. This article reviews the oral/systemic therapies as well as toxins that are used focally. Although medication can also be administered via intrathecal pumps, this treatment approach is discussed elsewhere.