This chapter explores the cellular and genetic mechanisms important in the development of neuropathic pain and other forms of chronic pain related to the phenomenon of sensitization. Peripheral sensitization contributes to pain hypersensitivity found at the location of tissue damage and/or inflammation. The chapter reviews the events that underlie pain as well as the anatomical and pharmacological basis for nociceptive sensations and chronic pain. Nociceptor excitation via various transient receptor potential (TRP) channels can result from a number of contributing processes. Transduction of mechanical, thermal, and chemical stimuli begins with membrane depolarization, which, if sufficient, transforms into an action potential. There are three classes of cell surface proteins at the sensory neuron important for sensory transduction: ion channels, metabotropic G protein-coupled receptors (GPCRs), and receptors for neurotrophins or cytokines. An important concept in central modulation of pain is the central inhibitory pathways and networks.