Summary: To explore the function of genes expressed by myelinating cells we have developed a model system that allows for the inducible ablation of predetermined genes in oligodendrocytes and Schwann cells. The Cre/loxP recombination system provides the opportunity to generate tissue-specific somatic mutations in mice. We have used a fusion protein between the Cre recombinase and a mutated ligand-binding domain of the human estrogen receptor (CreERT) to obtain inducible, site-specific recombination. CreERT expression was placed under the transcriptional control of the regulatory sequences of the myelin proteolipid protein (PLP) gene, which is abundantly expressed in oligodendrocytes and to a lesser extent in Schwann cells. The CreERT fusion protein translocated to the nucleus and mediated the recombination of a LacZ reporter transgene in myelinating cells of PLP/CreERT mice injected with the synthetic steroid tamoxifen. In untreated animals CreERT remained cytoplasmic, and there was no evidence of recombination. The PLP/ CreERT animals should be very useful in elucidating and distinguishing a particular gene's function in the formation and maintenance of the myelin sheath and in analyzing mature oligodendrocyte function in pathological conditions. genesis 35:63–72, 2003. © 2002 Wiley-Liss, Inc.