A very brief description will be given of recent findings from dissociated nociceptor cell bodies using whole-cell patch recording methods and single-cell imaging of the activity of critical enzymes in cell signaling pathways (providing new detail about mechanisms required for spontaneous activity in neuropathic pain conditions). Then, evidence will be presented in greater detail for a critical role of irregular depolarizing spontaneous fluctuations of membrane potential for hyperactivity of isolated nociceptors linked to persistent pain in rodents and humans. Some of the mechanisms, including contributions of multiple ion channels and cell signaling pathways, have interesting implications (both encouraging and potentially discouraging) for efforts to treat non-evoked pain. Electrophysiological specializations of nociceptors altered in neuropathic conditions, notably an increase in low-frequency large depolarizing spontaneous fluctuations and high membrane resistance, can inform optimized approaches to assess nociceptor excitability properties in human patients.