One of the paradoxes of human life is that the redox reactions that keep us alive generate products that can harm us. Thus, the balance of redox reactions is important in human health. Moreover, the etiology of many diseases, from dementia to diabetes, is thought to involve some form of redox imbalance, which could be oxidative or reductive stress. The measurement of antioxidant activity in physiological samples is of prime importance to many researchers in health and nutrition. An emerging view is that the effects of consumed antioxidants may arise from signal transduction rather than from absorption, and this may explain the difference between tests that demonstrate natural compounds with large physiological effects, but negligible or no absorption. Issues with cell and tissue assays are discussed including the assumption that stress in vivo produces the same chemistry as stress induced externally. Consideration is also given to compounds produced in cells compared to the same compounds absorbed from external exposure and whether they target the same sites in the cells, and whether changes occur indirectly due to signal transduction or via direct access. This chapter will give a brief overview of the current state of knowledge in this area by exploring differences in innate vs induced chemistry, as well as a critical assessment of procedures, and recommendations on what to do, why and how.