Endemic Burkitt lymphoma (BL) was publically described in 1958 and remains the most prevalent pediatric cancer in equatorial Africa with an annual incidence between two and five cases per 100,000 children. Several risk factors have been identified, including early-age infection with Epstein–Barr virus, a geographic association with high Plasmodium falciparummalaria transmission, and poor nutrition. However, other modifiable factors play a role in the survival of these children. Treatment regimens for BL have evolved over a time period that spans nearly 50 years. This review will compare survival between different combination chemotherapeutic regimens and discuss other key determinants of outcomes among children diagnosed with BL in resource-limited settings. A discussion of obstacles to diagnosis will be presented, including low community awareness of pediatric cancer, limited access to health facilities, inaccurate or delayed diagnosis often beginning at lower level health rural facilities that are typically staffed by those with limited training in oncology, and insufficient pathology support to confirm diagnosis. Other challenges examined here include those related to treatment adherence, specifically the social and economic stressors that can lead to abandonment of care, and treatment-related toxicity, a challenge compounded not only by the scarcity of medications for supportive care, but also the paucity of clinically trained medical professionals available to manage integrated care for these children. Future directions for enhancing BL survival will be discussed including molecular approaches for rational drug discovery as well as the benefits of forming a unified, global BL research network.