The epilepsies are one of the most common neurologic disorders with a diversity of etiologies. Despite tremendous advances in both medical and surgical therapies, availability of preventive and disease-modifying therapies is an important unmet medical need. Insight into the molecular and cellular mechanisms underlying epileptogenesis will hopefully provide novel targets for such therapies. To this end, multiple investigations using a variety of acquired epilepsy models deploying diverse etiologies (traumatic, ischemic, or seizure-induced) have identified the neurotrophin BDNF and its cognate receptor TrkB as key molecules in the pathogenesis. However, as detailed in this chapter, BDNF/TrkB signaling plays unique roles in each model. In addition to its contributions to epileptogenesis, BDNF/TrkB signaling contributes to neuronal survival following some epilepsy-inducing insults. Selective inhibition of distinct signaling pathways downstream of TrkB enables limiting TrkB-mediated epileptogenesis while preserving the protective functions. This chapter provides a critical review of the data supporting this diversity of roles for both BDNF and TrkB in the epilepsies and proposes strategies to disentangle these varying roles to develop therapies appropriate for clinical application.