Conversely to normal cells, where deregulated oxidative stress drives the activation of death pathways, malignant cells exploit oxidative milieu for its advantage. Cancer cells are located in a very complex microenvironment together with stromal components that participate to enhance oxidative stress to promote tumor progression. Indeed, convincing experimental and clinical evidence underline the key role of oxidative stress in several tumor aspects thus affecting several characteristics of cancer cells. Oxidants influence the DNA mutational potential, intracellular signaling pathways controlling cell proliferation and survival and cell motility and invasiveness as well as control the reactivity of stromal components that is fundamental for cancer development and dissemination, inflammation, tissue repair, and de novo angiogenesis. This paper is focused on the role of oxidant species in the acquisition of two mandatory features for aggressive neoplastic cells, recently defined by Hanahan and Weinberg as new “hallmarks of cancer”: tumor microenvironment and metabolic reprogramming of cancer cells.