The presence of activated oncogenes and/or inactivated tumor suppressor genes may result in constitutive activation of multiple transcription factors. This may be especially true in the early stages of tumor development. At advanced stages, however, uncontrolled tumor growth and the consequent development of a stress microenvironment, such as hypoxia, acidosis, and free radical overproduction, may further alter the activity of these transcription factors. Abnormal activation of and interplay between these factors lead to aberrant expression of multiple metastasis-related proteins and confer a tremendous survival and growth advantage to emerging metastatic variants. Understanding the expression and regulation of these molecules may shed more light on the biology of cancer metastasis as well as suggest new preventive and therapeutic approaches.