Chronic kidney disease (CKD) is a major complication of diabetes, affecting approximately 30–40% of patients. In many cases, CKD progresses to end-stage renal disease (ESRD). The peptide apelin and its receptor, APLNR, which is expressed in the endothelial cells of renal blood vessels, play a key role in glucose uptake and the regulation of vasodilation in the afferent and efferent glomerular arterioles. Numerous studies have demonstrated that the apelinergic system is dysregulated in various pathologies, including CKD in people with diabetes. In recent years, the apelinergic system has emerged as a promising therapeutic target for several diseases, with various apelin analogs and inhibitors being developed. In this review, we summarize the most recent literature on apelin and its cellular mechanisms of action, highlighting the role of the apelinergic system in various pathologies and its impact on patients with CKD and diabetes. Additionally, we explore the currently available analogs and inhibitors and discuss their potential therapeutic applications.