S100P is an EF-hand calcium-binding protein that was originally identified in placenta and subsequently associated with cancer. It is a member of S100 family of proteins that function as extracellular and/or intracellular regulators of diverse cellular processes and participate in various human pathologies. S100P expression was detected in a spectrum of human tumor cell lines and tissues derived from breast, prostate, pancreas, lung and colon, where it was connected with malignant phenotype, hormone independence and resistance to chemotherapy. Overexpression of S100P was shown to promote tumorigenesis and metastasis in diverse cancer models. Functional studies of S100P indicate that its biological activities are exerted through extracellular signaling via RAGE receptor, resulting in increased proliferation and survival, or through intracellular interaction with ezrin, leading to increased cell migration and metastasis. Molecular mechanisms regulating expression of S100P in cancer cells are just emerging. Besides earlier described DNA methylation, recent studies implicate bone morphogenic protein and non-steroidal anti-inflammatory drugs in control of S100P expression during tumor progression. Functional analysis of S100P promoter identified SMAD, STAT/CREB and SP/KLF binding sites as key regulatory elements participating in transcriptional activation of S100P gene in cancer cells. Moreover, the most recent data reveal that expression of S100P is up-regulated by activation of glucocorticoid receptor suggesting that S100P could play a role in therapy resistance mediated by glucocorticoids in solid tumors. Elucidation of S100P regulation is an important step towards understanding biological significance of its tissue distribution and proposing strategies for targeted S100P modulation.