S100A2 is a member of the EF-hand motif family S100. Its role has been recently implicated in carcinogenesis and metastasis. Although its precise role in NSCLC patients is debated and conflicting results have been published, it has been associated with patient survival. S100A2 expression was downregulated in some studies while others disagree that S100A2 is strongly expressed in lung cancer. It has been recently published by Hountis et al. that there is a significant association between nuclear S100A2 positivity and better disease-free interval. Intensity of expression was the highest in the early and advanced stages, and equally distributed in the middle stages. This is indicative for a dual role of this protein in carcinogenesis. The expression of S100A2 in operable NSCLC varies widely, and this differential location and expression pattern (nuclear or cytoplasmic or both) seem to correlate with prognosis. The precise role for the movement of S100A2 protein between cytoplasm and nucleus is still unclear. We present here a literature review, and we propose the dual concept on its substantial role as a prognostic or predictive indicator in this unfavorable group of patients.