Oxidative stress is linked with many pathologies ranging from cancer to neurodegenerative disorders and antioxidants
have presumably therapeutic value in such diseases. In this review, we categorize different direct and indirect
mechanisms by which antioxidants exert their action. These include scavenging and metal chelating effects, mimicking
the antioxidant enzymes or upregulation of their expression, activation of nuclear factor erythroid 2-related factor 2
(Nrf2), increasing the activity of sirtuins and inhibition of pro-oxidant enzymes among others. Recent findings on the
most frequently investigated antioxidants including polyphenolics, thiolics, spin trapping agents, SOD mimetics, inducers
of heme oxygenase-1 and nitric oxide synthase, activators of Nrf2, NADPH oxidase inhibitors and herbal supplements are
summarized. Furthermore, the antioxidant effects of drugs that are clinically used for other pharmacological purposes including
ACE inhibitors and statins are discussed. Cost-effectiveness and adverse effects of antioxidants are also evaluated.
Since antioxidant therapy has failed in many instances, we have classified the reasons that may explain these shortcomings
in different categories. Novel approaches to antioxidant therapy, that include mitochondria-targeting drugs, antioxidant
gene therapy and approaches for improvement of cell uptake and alteration of subcellular compartment localization
are also described. In the end, “shadows” that are shortcomings of antioxidant therapy as well as “lights” that include
positive outcomes are addressed. It is concluded that if we learn from failures, invest on agents with higher potential and
take advantage of novel emerging approaches, antioxidants could be an asset for the management of certain carefully chosen
oxidative stress-related diseases.