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/LCC-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 crossresistant to TAM. If similar resistance patterns are acquired in patients, a sequential modality with TAM 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.