Little is known about metastatic pathways that are specific to the lung rather than other organs. We previously showed that antioxidant proteins such as peroxiredoxins were specifically upregulated in lung metastatic breast cancer cells. We hypothesize that cancer cells that live under aerobic conditions, as might be the case in lungs, protect themselves against the damage caused by reactive oxygen species (ROS). To examine this hypothesis, we studied the role of peroxiredoxin-2 (PRDX2) in lung vs bone metastasis formation. A metastatic variant of MDA-MB-435 breast cancer cells that specifically metastasize to lungs (435-L3) was transduced with short hairpin RNAs to specifically silence PRDX2. Conversely, a bone metastatic variant of MDA-MB-231 cells (BO2) was stably transfected to overexpress PRDX2. The 435-L3 cells silenced for PRDX2 were significantly more sensitive to H(2)O(2)-induced oxidative stress than the parental and scrambled transfected cells. BO2/PRDX2 cells produced less ROS than BO2/green fluorescent protein control cells under oxidative stress. Moreover, PRDX2 knockdown inhibited the growth of 435-L3 cells in the lungs, whereas lymph node metastasis remained unaffected. In contrast, PRDX2 overexpression in bone metastatic BO2 breast cancer cells led to drastic inhibition of the skeletal tumor burden and reduction of bone destruction. Furthermore, PRDX2 expression in breast cancer cells was associated with a glucose-dependent phenotype, different from bone metastatic cells. Overall, our results strongly suggest that PRDX2 is a targetable 'metabolic adaptor' driver protein implicated in the selective growth of metastatic cells in the lungs by protecting them against oxidative stress.Oncogene advance online publication, 19 March 2012; doi:10.1038/onc.2012.93.