Although the neuropathological changes caused by severe or repeated seizures have been well characterized, many questions about the molecular mechanisms involved remain unanswered. Neuronal cell death, reactive gliosis, enhanced neurogenesis, and axonal sprouting are four of the best-studied sequelae of seizures. In vitro, each of these pathological processes can be substantially influenced by soluble protein factors, including neurotrophins, cytokines, and growth factors. Furthermore, many of these proteins and their receptors are expressed in the adult brain and are up-regulated in response to neuronal activity and injury. We review the evidence that these intercellular signaling proteins regulate seizure activity as well as subsequent pathology in vivo. As nerve growth factor and brain derived neurotrophic factor are the best-studied proteins of this class, we begin by discussing the evidence linking these neurotrophins to epilepsy and seizure. More than a dozen additional cytokines, growth factors, and neurotrophins that have been examined in the context of epilepsy models are then considered. We discuss the effect of seizure on expression of cytokines and growth factors, and explore the regulation of seizure development and aftermath by exogenous application or antagonist perturbation of these proteins. The experimental evidence supports a role for these factors in each aspect of seizure and pathology, and suggests potential targets for future therapeutics.