Sickle cell disease (SCD) is an inherited disorder that impairs red blood cells (RBCs) and disrupts the delivery of oxygen to tissues. There is currently no cure. Symptoms can appear as early as six months of age and include anemia, acute episodes of pain, swelling, infections, delayed growth, and vision problems. A growing number of therapies are being investigated for reducing these episodes of pain, also known as vaso-occlusive crises (VOCs). The research literature evidence, however, currently includes far more approaches that have not shown superiority versus placebo than ones that have been proven effective. The purpose of this systematic review is to evaluate the body of randomized controlled trials (RCTs) to determine the quality of support for and against the use of a variety of current and emerging therapies for treading SCD VOCs. Several important new papers have emerged since previous systematic reviews with similar objectives were published. This review was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and focused on PubMed exclusively. Only RCTs were sought, and no other filters, except for a five-year historical timeline cut-off, were used. Of the 46 publications that were returned in response to the query, 18 were ultimately accepted as meeting the pre-established inclusion criteria. The Cochrane risk-of-bias tool was utilized as a quality assessment measure, and the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) framework was used to assess the certainty of the evidence. Among the included publications, five out of 18 featured positive results with superiority and statistical significance versus placebo for either reduction in pain score or number/duration of VOCs. The approaches featured therapies ranging from de novo molecules to currently available drugs approved for other indications to naturally occurring metabolites such as amino acids and vitamins. A single therapy, arginine, was supported for both clinical endpoints: pain score reduction and shortened VOC duration. Currently, two therapies are approved by the United States Food and Drug Administration (FDA) and are commercially available (crizanlizumab, ADAKVEO and L-glutamine, Endari). All other therapies are investigational only in nature. Several studies included measurement of biomarker endpoints as well as clinical outcomes. Generally, beneficial outcomes related to improving biomarker levels did not also translate into statistically significant reduction of pain scores or number/duration of VOCs. While measuring biomarkers may contribute to the understanding of pathophysiology, it does not appear to directly offer predictive value toward treatment success clinically. It can be concluded that there exists a specific opportunity to design, fund, and execute investigations that both compare emerging and existing therapies versus one another and compare combinational therapies versus placebo.