Oxidative stress is a common denominator for many degenerative health ailments and the main component of ageing. Thus, several types of research are dedicated to combating this setback through pharmacological therapy and supplements. The study’s outcome showed a promising effect at the preclinical level but was unsatisfactory or controversial in clinical trials. This raises the need to understand the mechanistic evaluation of the therapeutic approach with possible challenges and limitations in targeting oxidative stress. Therefore, this chapter focuses on the role of oxidative stress in targeted areas, its assessment strategies with constraints, and possible challenges in pharmacological treatment strategies for generating better-emerging treatment strategies for decreasing disease load.