Accumulation of genetic and epigenetic alterations with inactivation of tumor suppressor proteins (PTEN, p53, p27 or Rb) and activation of oncogenic signaling (RTKs, PI3K/Akt and NF-κB) trigger the malignant transformation of normal tissue and transformation of normal stem/progenitor cells to tumorigenic cancer stem/progenitor cells. The gene discussed is RB1; the disease is cancer.