Androgen deprivation therapies for metastatic prostate cancer are useful initially, but progression to androgen independence usually results in relapse within 2 years. The molecular mechanisms underlying the clinically important transition from androgen dependence to androgen independence are poorly described. Several lines of investigation have suggested that insulin-like growth factors (IGFs) are involved in the biology of prostate cancer, but little is known about their relevance to progression to androgen independence. We used three in vivo models of androgen-dependent (AD) human prostate cancer to study this issue. Progression to androgen-independent (AI) growth was associated with a 60-fold increase in expression of IGF-I mRNA in LAPC-9 xenografts and a 28-fold increase in IGF-I expression in LNCAP xenografts, relative to the initial AD neoplasms. IGF type I receptor (IGF-IR) mRNA levels were approximately 2.5-fold and approximately 5-fold higher, respectively, in AI LAPC-9 and LNCaP tumors compared with the original AD neoplasms. AI growth of these xenografts was also associated with significant reductions in IGF binding protein-3 expression. LAPC-4 xenografts, which previously have been shown to exhibit molecular pathology related to HER-2/neu expression with progression to AI, showed relatively minor changes in expression of the genes investigated, but we nevertheless found evidence of increased IGF-IR phosphorylation with progression to androgen independence in this model. Taken together with prior observations, our results suggest that deregulation of expression of genes related to any one of several critical receptor tyrosine kinase regulatory systems, including IGF signaling, may confer androgen independence.