The mating of two parent strains of transgenic mice is needed to make progeny in which expression of a transgene encoding histone H2B-green fluorescent protein (H2B-GFP) can be turned off when tetracycline is added to the animal’s diet. The first parent strain harbors the H2B-GFP transgene under the control of a tetracycline (doxycycline; dox) regulatory element (TRE). The second expresses a transcription factor regulated by tetracycline (TetRVP16) that is under the control of a cell-type-specific promoter. In the first example shown, the keratin 5 (k5) promoter drives expression of TetRVP16 leading to expression of H2B-GFP in the skin epithelium until 4 weeks of age, at which time tetracycline is administered for 4 weeks so that dividing cells dilute out the label and differentiating cells are sloughed from the skin (Tumbar et al., 2004). In the second example, TetRVP16 driven by the promoter of the stem cell leukemia (SCL) gene is used to express H2B-GFP in hematopoietic stem cells (HSCs) and different multipotent progenitors (MPPs) of the hematopoietic system for 10–13 days, after which tetracycline is administered for 80 days to identify the label-retaining cells (LRCs) (Wilson et al., 2008). Schematic adapted from Nowak (2009).