Currently the clinical needs for pain and headache management are not met. Despite the numerous and exciting recent advances in understanding the molecular and cellular mechanisms that originate pain, we cannot yet fully explain the mechanism underlying the biology of chronic pain. Pain is a natural mechanism preserving our species survival; however, when the protective quality is lost, physiologic changes to the peripheral and central nervous systems result in the formation of chronic pain states. Once we understand how this chronic pain state is created, either through genetic, environmental, therapeutic, or other triggers we may be able to enhance our species existence, limiting maladaptive pain and suffering. The future therapeutic targets will need to address the genetics, neurophysiologic changes of the neurons and brain as well as help control immune systems including the glia. The key to successful headache and pain therapy is research aimed at prevention and minimizing the plastic changes triggering chronic pain.