The discovery that adult somatic cells can be reprogrammed into pluripotent cells by expressing a combination of factors associated with pluripotency holds immense promise for a wide range of biotechnological and therapeutic applications. However, some hurdles-such as improving the low reprogramming efficiencies and ensuring the pluripotent potential, genomic integrity and safety of the resulting cells-must be overcome before induced pluripotent stem cells (iPSCs) can be used for clinical purposes. Several groups have recently shown that key tumour suppressors-such as members of the p53 and p16(INK4a)/retinoblastoma networks-control the efficiency of iPSC generation by activating cell-intrinsic programmes such as senescence. Here, we discuss the implications of these discoveries for improving the safety and efficiency of iPSC generation, and for increasing our understanding of different aspects of basic biology-such as the control of pluripotency or the mechanisms involved in the generation of cancer stem cells.