Spasticity and hypertonicity are common components of the upper motor neuron syndrome (UMNS), which is seen in various neurologic conditions. Pharmacologic agents that can be administered through different routes can play an important part in treatment aimed at minimizing complications, pain, and functional deficits caused by UMNS. They can be administered by way of an oral, transdermal, intramuscular, or intrathecal route and can play an important role in the management of UMNS. This article reviews UMNS, the functional consequences that can result from it, individual agents, and their indications, complications, and adverse effects. Algorithms for treatment of UMNS with pharmacologic agents, and these agents' efficacy in different neurologic populations, is reviewed.