Insulin-like growth factors I and II are among the most abundant growth factors found in bone, and their expression also has been reported in a variety of neoplastic tissues. Using the technique of in situ hybridization, the authors have studied the expression of the messenger ribonucleic acid (mRNA) for insulin-like growth factors I and II and the Type 1 insulin-like growth factor receptor in giant cell tumors of human bone (n = 8). The expression of the mRNA for insulin-like growth factors I and II and the Type 1 insulin-like growth factor receptor was observed in giant cells and in the mononuclear stromal cell component but not in cells of the fibrous connective tissue at the growing edge of the tumor. The multinucleated cells expressed tartrate resistant acid phosphatase and showed reactivity with osteoclast selective monoclonal antibodies, confirming the close relationship between these giant cells and osteoclasts. Thus, these results are consistent with the possibility that locally produced insulin-like growth factors have an important regulatory role in the growth and development of giant cell tumors of bone. In addition, they suggest that these growth factors may function as autocrine or paracrine regulators of the proliferation and differentiation of cells of the osteoclast lineage.