Despite increasing numbers of patients on dialysis, the numbers of renal transplants performed yearly have remained relatively static. During the last 50 years, there have been many advances in the pharmacology of prevention of organ rejection. However, most patients will suffer from a slow but steady decline in renal function leading to graft loss. The most common cause of long-term graft loss is chronic allograft nephropathy (CAN). Therefore, elucidating and understanding the mechanisms involved in CAN is crucial for achieving better post-transplant outcomes. It is thought that the development of epithelial to mesenchymal transition (EMT) in proximal tubules is one of the first steps towards CAN, and has been shown to be a result of cellular senescence. Cells undergoing senescence acquire a senescence associated secretory phenotype (SASP) leading to the production of interleukin-1 alpha (IL-1α), which has been implicated in several degenerative and inflammatory processes including renal disease. A central mediator in SASP activation is the production of reactive oxygen species (ROS), which are produced in response to numerous physiologic and pathologic stimuli. This review explores the connection between SASP and the development of EMT/CAN in an effort to suggest future directions for research leading to improved long-term graft outcomes.