Despite more than 100 years of clinical observations and research, many unanswered questions remain in the management of sickle cell disease (SCD). While giant strides in the prevention of pediatric morbidity and mortality have been made in the past few decades, adults with SCD are faced with a chronic, debilitating disease with limited preventive and therapeutic options. Stem cell transplantation, the only cure presently available, and gene therapy, an emerging cure, are limited by toxicity, restricted eligibility, and high cost. Until 2017, hydroxyurea (FDA approved in 1998) and blood transfusion were the only disease-modifying therapies available for SCD. Recently, the therapeutic options have expanded with the addition of several disease-modifying therapies, including L-glutamine (approved in 2017), crizanlizumab (2019), and voxelotor (2019). The previously published National Heart, Lung, and Blood Institute (NHLBI) guidelines for the management of SCD (2014) and the recently published American Society of Hematology (ASH) guidelines (2019), both of which we strongly encourage the reader to review, provide a comprehensive compendium of the available evidence and evidence-based recommendations but necessarily rely heavily on expert panel consensus opinion in many areas. Thus, important preventive and therapeutic interventions remain controversial. By presenting the following cases, we have attempted to review the most important evidence-based guidelines and existing controversies in the prevention of SCD complications. Please note that we will follow the standard nomenclature of sickle cell anemia (SCA) to denote HbSS and HbS/β0 thalassemia and SCD to denote any disease subtype (HbSS, HbS/β0 or β+ thalassemia, HbSC, HbSD, and HbSO). We will use the term vaso-occlusive crisis (VOC) to denote a painful episode/pain crisis.