Primary hyperoxalurias (PHs) are a group of inherited alterations of the hepatic 
glyoxylate metabolism. PHs classification based on gene mutations parallel a 
variety of enzymatic defects, and all involve the harmful accumulation of 
calcium oxalate crystals that produce systemic damage. These geographically 
widespread rare diseases have a deep impact in the life quality of the patients. 
Until recently, treatments were limited to palliative measures and kidney/liver 
transplants in the most severe forms. Efforts made to develop pharmacological 
treatments succeeded with the biotechnological agent lumasiran, a siRNA product 
against glycolate oxidase, which has become the first effective therapy to treat 
PH1. However, small molecule drugs have classically been preferred since they 
benefit from experience and have better pharmacological properties. The 
development of small molecule inhibitors designed against key enzymes of 
glyoxylate metabolism is on the focus of research. Enzyme inhibitors are 
successful and widely used in several diseases and their pharmacokinetic 
advantages are well known. In PHs, effective enzymatic targets have been 
determined and characterized for drug design and interesting inhibitory 
activities have been achieved both in vitro and in vivo. This review describes 
the most recent advances towards the development of small molecule enzyme 
inhibitors in the treatment of PHs, introducing the multi-target approach as a 
more effective and safe therapeutic option.