Transcription Factors (TFs)' are commonly deregulated in almost all human cancers. The main causes of the altered expression of TFs are chromosomal translocations and TF encoding genes that suffer from amplification or deletion, point mutations, etc. These mechanisms directly alter the TF's status to gain or loss-of-function. Other main driving mechanisms that affect the TF regulation in cancer include mutation of TF cofactors and numerous oncogenic signal transduction cascades, leading the gene expression status to favor the cell transformation. Countless pathways and mechanisms of TF deregulation in cancer show that TFs play a central role in aberrant gene expression in cellular transformation and are a major class of cancer cell dependencies. As we already learned from successful cases of drugs that target nuclear hormone receptors, the targeting of TFs can be highly effective in treating certain cancers.