Cognitive impairment involves alterations to one's cognitive status that affects everyday life. Individuals with CKD, and particularly kidney failure, experience higher rates of cognitive impairment (20%–70%) compared with the general population. The highest prevalence is described in kidney failure such that dialysis-dependent patients have twice the prevalence of age-matched controls. In the past 5 years, the number of investigations examining the “kidney-brain axis,” mechanisms of CKD-related cognitive impairment, and potential therapeutics have exponentially increased. This review article summarizes recent literature on direct and indirect effects of CKD-associated cognitive impairment with emphasis on uremic toxins; brain injury mechanisms; overlap between CKD-associated cognitive impairment, Alzheimer's disease, and other neurodegenerative diseases. Reviewed therapeutic interventions include AST-120 (indoxyl sulfate absorbent), CH-223191 (aryl hydrocarbon receptor antagonist), triarylmethane-34 (Kca3.1-specific inhibitor), anakinra (IL-1R inhibitor), marimastat, exercise, supplements, and kidney transplantation. Special focus is placed on translational studies examining uremic toxin–associated pathogenic processes, including brain oxidative stress, neuroinflammation, and blood-brain barrier dysfunction through in vitro and in vivo models of CKD-associated brain injury. Finally, future research directions are suggested, including targeting of cellular senescence abundance with senotherapeutics and capitalizing on anti-inflammatory effects of regenerative, cell-based therapeutics ( e.g ., mesenchymal stem cells and extracellular vesicles), and use of aged murine models. Collectively, CKD-associated cognitive impairment represents a prevalent condition for which remaining knowledge gaps exist, and scientific advancements are needed to preserve cognitive function and improve the lives of individuals with CKD.