Pain is a fundamental and central life experience, a counterbalance to pleasure, a warning of danger, and a reminder to guard injured limbs and tissues while they heal. And yet, however beneficial pain may be to our physiological well-being, it is also the most acutely unpleasant of sensations and one of the primary reasons patients seek medical care. Pain ranges in intensity from annoying, dull aching to throbbing, burning, sharp, or stabbing. At its worst, intractable combinations of these phenotypes are experienced by some cancer patients and others suffering chronic ailments. Scientific research and medical practice have coined a number of terms to describe pain in terms of its origins, manifestations, and chronicity. While attempts to understand the origins and control of pain date from antiquity, over the past 20 years, the expansion of molecular and cellular biology knowledge has led to the creation of tools that have allowed scientists to develop a much more detailed understanding of what causes pain and how it is transmitted, processed, and perceived individually, including our homeostatic control mechanisms. Most importantly, it also has helped identify a large number of potential targets for drug discovery. Unfortunately, despite our present depth of knowledge and a number of key mechanisms identified as intervention points, chronic pain and, in particular, neuropathic pain remain a greatly underserved medical need. Part of the difficulty in developing effective treatments for chronic pain lies in our failure to resolve the complex interplay among mechanisms involved. Unlike many other diseases, pain is not controlled by a “master gene” or target that can dominate the many viable mechanisms influencing pain signal initiation and transmission. In addition, because in many cases the most effective therapeutic agents for particularly neuropathic pain will be those that gain access to the central nervous system (CNS), the field has struggled to develop drugs that provide relief devoid of central side effects such as dizziness and drowsiness that limit the patient’s ability to carry out normal activities. The scope of this review is to briefly cover some basic concepts encapsulating our current understanding of pain, including the molecular complexity involved in generating pain. In addition, the distinctions (and overlap) between acute nociceptive, chronic inflammatory, and neuropathic pain will be highlighted with the goal of providing a background for the following articles in this series that focus on a few key mechanistic targets currently being exploited in hopes of developing effective, safe, and tolerable pharmacotherapies for the treatment of neuropathic pain.