Acute Kidney Injury (AKI) - a sudden episode of kidney failure - affects millions of patients each year, including nearly 60% of those in intensive care units. Some patients do not recover and progress to chronic kidney disease (CKD), and eventually require dialysis or renal transplant. Those who do recover are often left with kidney fibrosis, and are at increased risk of developing CKD later. Currently, there are no approved drugs that specifically target AKI, nor prevent or reduce post-injury progression to CKD. There remains, therefore, a critical need for AKI-specific treatments that hasten recovery, promote kidney repair and reduce the risk of CKD development. We discovered that selective HDAC8 inhibitors resolve AKI and reduce the resultant kidney damage after the onset of injury across multiple in vivo AKI models. This talk will describe our work on developing and optimizing several series of novel HDAC8 inhibitors, including molecules that indirectly modulate HDAC8 function, as well as active site inhibitors that lack the hydroxamic acid moiety – a functional group common to many HDAC inhibitors and associated with toxicity.