Neuropathic pain therapy remains enormously challenging despite the increases in knowledge of pain etiology and mechanisms drawn from animal studies. Mechanism-based discovery underlies key approaches toward reduction of peripheral and central hyperexcitability. These include a number of poorly validated molecular targets, such as ion channels, G-protein coupled receptors, purinergic receptors, and chemokine receptors, as well as downstream regulators of protein phosphorylation. Improvement in translating these approaches into the development of drugs for use in the pain clinic remains a significant but surmountable challenge. Keywords: adenosine triphosphate, fructalkine, G-protein coupled receptors, ion channels, kinase