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Nabin Raj Karki, Abdullah Kutlar Division of Hematology/Oncology, Augusta University, Augusta, GA, USACorrespondence: Nabin Raj KarkiDivision of Hematology Oncology, Georgia Cancer Center at Augusta University, 1410, Laney Walker Blvd, CN 5347, Augusta, GA, 30912, USATel +1-706-721-2505Fax +1-706-721-5566Email nkarki@augusta.eduAbstract: Microvascular vaso-occlusion driven pain crisis is the hallmark of sickle cell disease with profound morbidity and increased mortality. Selectins, most notably P-selectins have an integral role in this phenomenon. P-selection was first identified in 1989. In 2019, after 3 decades of basic, translational, and clinical work with this pathway, the US Food and Drug Administration approved a P-selectin antibody, crizanlizumab to reduce frequency of pain crisis in patients more than 16 years with sickle cell disease. We review the fundamentals of P-selectin pathobiology, P-selectin blocking agents, clinical data with the use of crizanlizumab and prospects of this novel class of drugs in the context of other treatments for painful vaso-occlusive episodes.Keywords: P-selectin, sickle cell disease, pain crisis, crizanlizumab