Metallothioneins (MTs) are low molecular, cysteine-rich proteins that have naturally-occurring Zn2+ in both clusters. They may serve as a reservoir of metals for synthesis of apoenzymes and zinc-finger transcription regulators. MTs are also involved with several important proteins e.g. p53, NF-κB, PKCl, and GTPase Rab3A. New biological roles for these proteins have been identified including those needed in the carcinogenic process. However, their use as a predictive marker remains controversial. Several reports have disclosed MTs expression as a prognostic factor for tumor progression and drug resistance in a variety of malignancies particularly breast, prostatic, ovarial, head and neck, non-small cell lung cancer, melanoma, and soft tissue sarcoma. The role of MTs as a tumor disease marker or as a cause of resistance in cancer treatment is reviewed and discussed. Moreover, we describe some analytical methods that were developed to detect MTs.