The prevalence of anemia in chronic kidney disease (CKD) patients is almost twice that of the normal population and its severity increases exponentially as the disease worsens, dramatically affecting the quality of an individual's life. The advent of erythropoiesis stimulating agents (ESA) in the 1980s saw a revolutionary change in the treatment of anemia in CKD patients, drastically improving quality of life (QoL), overall health and reducing the need for blood transfusions. Numerous ESAs have been developed ever since and are in current use, with the primary routes of administration being intravenous (IV) and subcutaneous (SC) injections. Their use, however, has stirred significant controversy over the last two decades. Additionally, despite numerous studies and trials, the latest international recommendations for their use do not provide clear cut guidance with well-grounded evidence on the recommended route of administration for different sets of patients. Instead, this decision has mainly been left up to the physician's discretion, whilst keeping certain key factors in mind. This review shall summarize, discuss and compare the findings of previous studies on various factors governing the two aforementioned routes of administration and identify areas that need further exploration.