Understanding the hydrolytic degradation of PLA is crucial for medical applications, for an optimal degradation rate as pharmaceutical matrices and for the plastics industry to meet the current environmental regulations. The aim of this chapter is to review the recent studies reported in the literature on the mechanisms and parameters of abiotic-hydrolytic degradation of PLA. In general, it has been stated that the PLA degradation mechanisms and reaction rates seem to be affected by a wide variety of compositional and property variables, e.g. matrix morphology, shape and geometry, molecular weight, chemical composition, stereochemical structure, chain orientation, crystallinity, presence of additives, nanoparticles or other polymer matrices, and by environmental degradation conditions, such as medium pH and temperature. A possible partial control of the hydrolytic degradation of PLA by varying the above parameters has been evidenced, which is very useful for determining biomedical or ecological applications without compromising the properties of PLA-based products prior to the onset of degradation. Further possible advantages in the structural, thermal, crystalline, mechanical and degradative properties of PLA-based materials upon their hydrolytic degradation are here identified, enabling their wider use in industrial, biomedical and environmental applications.