End-stage renal disease (ESRD) continues to be a disease process with a high rate of hospitalization and mortality. There has been little innovation in nephrology over the last few decades compared to revolutionary high-tech advancements in other areas like oncology and cardiovascular medicine. Kidney transplantation, the only available alternative to renal replacement therapy, is limited in its availability. It is essential to have advances in this field to improve the efficiency of currently available treatments and devise new therapies. The current description of renal replacement therapy is inappropriate as it only replaces the filtration function of the failed kidney without addressing its other vital metabolic, endocrinologic, and immunologic roles and portability. Hence, it is critical to have newer therapies focusing on total replacement and portability, not just clearance. This review will address the developments in hemodialysis therapy. Advances in hemodialysis therapy include hemodiafiltration, portable machines, wearable artificial kidneys, and bioartificial kidneys. Although promising, newer technologies in this direction are still far from clinical application. Several organizations and enterprises including the Kidney Health Initiative and Kidney X: The Kidney Innovation Accelerator, as well as The Advancing American Kidney Health Initiative, are working in tandem to develop new therapies that could customize the treatment of ESRD.