The debate about the management of pain in the neonate has continued to evolve over the past 30 years. This controversy can be understood as evolving through now three eras of thought about the effect of pain and its management in newborns and infants. The first generation was characterized by a widespread belief that newborns lacked the complete development of the neuroanatomical and neuroendocrine components necessary to perceive pain. During this period, newborns often received inadequate anesthesia and analgesia for painful procedures, if not no treatment at all. The second generation was heralded by research that demonstrated that newborns did demonstrate similar or even exaggerated physiological and hormonal responses to pain compared with those observed in older children and adults and that exposure to prolonged or severe pain may increase neonatal morbidity. Controversy in this generation focused around the dosage of analgesia to newborns as well as the risks and benefits of pain management techniques. We are now in a third generation of thought about pain in the neonate, defined by intense debate over the significance of a growing number of studies in immature animal models that demonstrate degenerative effects of several anesthetics on neuronal structure. The challenge of this era is to integrate the advances in diagnosis and treatment achieved in previous generations with ongoing adaptation of clinical practice as dictated by research advances in the field. In this review, we examine the evolution of medical thought and ethical concerns regarding pain treatment in the neonate.