The role of the tight junctions (TJ) in controlling paracellular traffic of ions and molecules, through the regulation of claudin proteins, is now established. However, it has also become increasingly evident that claudin proteins, as integral components of the TJs, play crucial role in maintaining the cell–cell integrity. In conformity, deregulation of claudin expression and cellular distribution in cancer tissues has been widely documented and correlated with cancer progression and metastasis. However, this correlation is not unidirectional and rather suggests tissue specific regulations. Irrespective, if the widely described correlations between altered claudin expression and cancer initiation/progression could be established, they may serve as important markers for prognostic purposes and potential therapeutic targets. In this review, we summarize data from screening of the cancer tissues, manipulation of claudin expression in cells and animals subjected to cancer models, and how claudins are regulated in cancer. The focus of this article remains analysis of the association between cancer and the claudins and to decipher clinical relevance.