AbstractTo study the physiological control of osteoclasts, the bone resorbing cells, we generated transgenic mice carrying the Cre recombinase gene driven by either the tartrate‐resistant acid phosphatase (TRAP) or cathepsin K (Ctsk) promoters. TRAP‐Cre and Ctsk‐Cre transgenic mouse lines were characterized by breeding with LacZ ROSA 26 (R26R) reporter mice and immunohistochemistry for Cre recombinase. The Cre transgene was functional in all lines, with Cre‐mediated recombination occurring primarily in the long bones, vertebrae, ribs, and calvaria. Histological analyses of the bones demonstrated that functional Cre protein was present in 1) osteoclasts (Ctsk‐Cre); 2) osteoclasts, columnar proliferating, and hypertrophic chondrocytes (TRAP‐Cre line 4); and 3) round proliferating chondrocytes (TRAP‐Cre line 3). In conclusion, we generated transgenic mouse lines that will enable the deletion of floxed target genes in osteoclasts, which will be valuable tools for studying the regulation of osteoclast function. genesis 39:178–185, 2004. © 2004 Wiley‐Liss, Inc.