Kruppel-like factors (Klf) 4 and 5 belong to a family of zinc finger-containing transcription factors that share homology with the Drosophila gene Kruppel. They regulate proliferation and differentiation of a wide variety of cells and have been linked to tumorigenesis. Their most striking role so far has turned out to be their ability to reprogram/ maintain embryonic stem cell fate. In this review, the data available in the field regarding their role in proliferation and differentiation and their coupling to carcinogenesis are summarized. The emphasis is on their context dependence and how they might be able to regulate diverse transcriptional outputs from the genome.