Voltage-gated sodium channels underpin electrical signaling in sensory neurons. Their activity is an essential element in the vast majority of pain conditions, making them significant drug targets. Sensory neuron sodium channels play roles not only in afferent signaling but also in a range of efferent regulatory mechanisms. Side effects through actions on other cell types and efferent signaling are thus important issues to address during analgesic drug development. As an example, the human genetic evidence for NaV1.7 as an ideal pain target contrasts with the side effects of NaV1.7 antagonists. In this review, we describe the history and progress toward the development of useful analgesic drugs and the renewed focus on NaV1.8 as a key target in pain treatment. NaV1.8 antagonists alone or in combination with other analgesics are likely to provide new opportunities for pain relief for the vast number of people (about 33% of the population) impacted by chronic pain, particularly present in aging populations.