Biological milieus are highly crowded and heterogeneous systems where organization of macromolecules within nanodomains (e.g. membraneless compartments) is vital to the regulation of metabolic processes. There is an increasing interest in understanding the effects that such packed environments have on different biochemical and biological processes. In this context, the redox biochemistry and redox signaling fields are moving towards investigating oxidative processes under conditions that exhibit these key features of biological systems in order to solve existing paradigms including those related to the generation and transmission of specific redox signals within and between cells in both normal physiology and under conditions of oxidative stress. This review outlines the effects that crowding, nanodomain formation and altered local viscosities can have on biochemical processes involving proteins, and then discusses some of the reactions and pathways involving proteins and oxidants that may, or are known to, be modulated by these factors. We postulate that knowledge of protein modification processes (e.g. kinetics, pathways and product formation) under conditions that mimic biological milieus, will provide a better understanding of the response of cells to endogenous and exogenous stressors, and their role in ageing, signaling, health and disease.