The sigma receptor was first described as a novel opioid receptor but later found to be a distinct pharmacological entity distinguished by its unusually promiscuous ability to bind a wide variety of drugs (Martin et al. 1976). Binding of antipsychotic drugs such as haloperidol, along with a genetic linkage to schizophrenia, implicate sigma receptors also in psychosis (Ishiguro et al. 1998). In the central nervous system (CNS), sigma receptors have been shown to be involved in regulation of neurotransmitter release, modulation of neurotransmitter receptor function, learning and memory processes, and regulation of movement and posture (Su et al. 1993) as well as ion channel modulation (Aydar et al. 2002) sigma receptors have been implicated in cancer (Aydar et al. 2004). However the mechanisms through which sigma receptors produce their effects are still being defined. Expression of sigma1 receptors in various human cell lines of different metastatic potential was investigated using real time (RT) PCR and by western blotting with a sigma1 receptor specific antibody. We tested the effect of sigma1 and sigma2 specific drugs on proliferation, adhesion, endocytosis and motility on two breast cell lines of different metastatic potential and a normal breast cell line. Subsequently we constructed and tested sigma1 receptor gene silencing and sigma1 receptor over-expression constructs. Our results indicate that: 1) Metastatic cells express higher levels of sigma1 receptors than corresponding normal cells (4%), with the degree of sigma1 expression correlating with the degree of metastasis of the cell line (17-84%). 2) Silencing or over-expression of sigma1 receptor gene produced significant changes in cell proliferation for breast cancer cell lines (silencing; 6 ± 0.6%, 19 ± 1.9% and 13 ± 1.9% for MCF-10A, MCF-7 and MDA-MB-231, and over-expression; 20 ± 2.4% and 22 ± 0.4% for MCF-7 and MDA-MB-231), and less significant changes for non-cancer breast cell lines. 3) Over- expression or silencing of sigma1 receptor gene resulted in significant reductions in cellular adhesion for breast cancer cell lines (over-expression; 30 ± 5.5%, 18 ± 2.6% and 28 ± 1.6% for MCF-10A, MCF-7 and MDA-B231, knockdown; 19 ± 4.7%, 13 ± 1.7% and 13 ± 0% for MCF-10A, MCF-7 and MDA-MB-231) and a less significant reduction in adhesion in a normal breast cell line. Overall, we conclude that sigma receptors may play significant roles in the proliferation and adhesion of breast cancer cells. Our results are discussed in the light of recent advances in the understanding of sigma receptor biology.