After a brief historical overview of the development of three families of poly(otho esters) (POEs), the physico-chemical characteristics, drug release properties and biocompatibility of the third generation is discussed. Its synthesis is based on a transesterification reaction between 1,2,6-hexanetriol and trimethylorthoacetate. This viscous hydrophobic polymer has been used for the sustained release of 5-fluorouracil (5-FU) or mitomycin C (MMC) in glaucoma filtering surgery. It shows a good correlation between drug release and polymer erosion and can be injected using a hydraulic syringe. Drug release can be modulated by using different molecular weights of the polymer, or by adding basic or acidic excipients. Because conventional sterilization methods using gamma or electron beam-irradiation can not used due to changes in molecular weight and dynamic viscosity resulting from backbone cleavage, an aseptic fabrication procedure has been developed and validated. POE biocompatibility has been established after subconjunctival injections of POE, monomers and degradation products in rabbits. Better control of the microenvironmental pH during polymer degradation has been achieved by using an in situ formed buffer system.