Pain is the most characteristic feature of sickle cell disease (SCD). Patients with SCD live with unpredictable, recurrent episodes of acute painful crisis, as well as chronic unremitting pain throughout their lifetime. While most of the research and medical efforts have focused on treating vaso-occlusion crisis and acute pain, chronic pain remains a significant challenge faced by patients and physicians. Emerging evidence from human and animal studies has suggested the presence of a neuropathic component in SCD pain. New knowledge on the neurobiology of chronic pain in SCD has significant implications in unraveling the underlying mechanisms. This review focuses on the recent advances on the role of protein kinase C or PKC in promoting and maintaining chronic pain conditions. With a highlight of a specific PKC isoform, PKCδ, we aim to propose PKC as an essential regulator of chronic pain in SCD, which may ultimately lead to innovative therapeutic strategies for treating this devastating life-long problem in patients with SCD.