Abstract Chronic inflammation and oxidative stress, features that are closely associated with nuclear factor (NF-κB) activation, play a key role in the development and progression of chronic kidney disease (CKD). Several animal models and clinical trials have clearly demonstrated the effectiveness of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy to improve glomerular/tubulointerstitial damage, reduce proteinuria, and decrease CKD progression, but CKD treatment still represents a clinical challenge. Bardoxolone methyl, a first-in-class oral Nrf-2 (nuclear factor erythroid 2-related factor 2) agonist that until recently showed considerable potential for the management of a range of chronic diseases, had been shown to improve kidney function in patients with advanced diabetic nephropathy (DN) with few adverse events in a phase 2 trial, but a large phase 3 study in patients with diabetes and CKD was halted due to emerging toxicity and death in a number of patients. Instead, palmitoylethanolamide (PEA) a member of the fatty acid ethanolamine family, is a novel non-steroidal, kidney friendly anti-inflammatory and anti-fibrotic agent with a well-documented safety profile, that may represent a potential candidate in treating CKD probably by a combination of pharmacological properties, including some activity at the peroxisome proliferator activated receptor alpha (PPAR-α). The aim of this review is to discuss new therapeutic approaches for the treatment of CKD, with particular reference to the outcome of two therapies, bardoxolone methyl and PEA, to improve our understanding of which pharmacological properties are responsible for the anti-inflammatory effects necessary for the effective treatment of renal disease.