Cancer has a complex etiology with multiple risk factors that involve the interplay between genetic and environmental influences. There is compelling evidence that dietary plant foods appear to be protective against certain type of cancers. Among a number of mechanistic hypotheses, diet-derived antioxidants have been proposed to contribute to explain these findings. However, contrasting results from intervention trials have raised strong concerns about the influence of antioxidants on human health. A vulnerable point of the research on antioxidants is the lack of information on the effect of the whole array of dietary antioxidants in cancer prevention because so far mainly single molecules have been investigated. Total antioxidant capacity (TAC) considers the single antioxidant activity as well as the synergistic interactions of the redox molecules present in complex matrixes, giving an insight into the assessment of the non-enzymatic antioxidant network. This article will outline the state of art of the research on TAC and cancer, describing the plasma non-enzymatic antioxidant network and its association with diet. The feasibility of TAC assessment as an innovative tool for investigating the association between dietary antioxidants, oxidative stress, and cancer will be also discussed.