Significance: We herein review recent advances on the role exerted by protein redox machines engaged in tumor progression, focusing on cell adhesion and migration, regulation of transcriptional response, and tumor metabolic reprogramming, all features belonging to the new hallmarks of cancer. Recent Advances: Several recent insights have reported that oxidative stress, either due to intracellular sources of oxidants, which are frequently deregulated in cancers or to microenvironment factors as hypoxia or stromal cell contact, plays a key role in tumor malignancy, as well as in metabolic pathways control. Indeed, many proteins behave as sensors of intracellular oxidative stress, including protein tyrosine kinases and phosphatases, transcription factors as p53, forkhead box class-Os, nuclear respiratory factor-2, nuclear factor-kB, hypoxia inducible factor, enzymes involved in glycolysis or penthose phosphate pathway as pyruvate kinase-M2 and adenylate monophosphate kinase, or DNA repair enzymes as Ataxia Teleangectasia Mutated. All these proteins have been reported to play essential roles during cancer progression and their sensitivity to oxidative stress has added new levels of complexity to the cancer field. Critical Issues: Main significant issues that need to be addressed in redox cancer biology are (i) sensitivity to a different level of oxidative stress of sensors, that is, they can respond to different oxidative insults/signals, and (ii) the real susceptibility of cancer cells to redox-based therapies due to the acknowledged plasticity of cancer cells to develop adoptive strategies. Future Directions: Definitely, redox machines have the potentiality to develop into novel biomarkers and related target therapies should attain the goal of personalized medicine in the fight against cancer. Antioxid. Redox Signal. 19, 1828–1845.