Almost all initially responsive breast tumors acquire resistance to the triphenylethylene antiestrogen tamoxifen (TAM). Development of resistance represents the major restriction in the current use of TAM. More recently, a series of steroidal antiestrogens have been developed (e.g. ICI 182,780), and we wished to determine whether cross-resistance among these drugs occurs, and what the likely mechanisms of resistance are. We have further selected breast cancer variant cell lines that no longer require estrogens for growth (MCF-7/LCC-1) against either 4-hydroxytamoxifen (MCF-7/LLC-2) or ICI 182,780 (MCF-7/LCC-9). Analysis of the resistance phenotypes suggests that TAM resistant cells can retain responsiveness to the steroidal antiestrogens, whereas cells selected against ICI 182,780 are cross-resistant to TAM. If similar resistance patterns are acquired in patients, a sequential modality with TAN as the first-line and ICI 182,780 as a second-line drug, is suggested. We have generated a gene-network hypothesis to explain these differential resistance patterns and outline their potential molecular mechanisms.