The estrogen receptors (ERs) belong to the nuclear receptor superfamily, and as such act as ligand inducible transcription factors, mediating the effects of estrogens. However, their pharmacology is complex, having the ability to be differentially activated by ligands. Such ligands possess the ability to behave as either ER-agonists or ER-antagonists, depending on the cellular and tissue context, and have been termed Selective Estrogen Receptor Modulators (SERMs). Several SERMs have been identified with clinical relevance such as tamoxifen and raloxifene. Recently, 27-hydroxycholesterol has been characterized as the first identified endogenous SERM leading to the notion that other endogenous SERMs may exist, each having potential pathophysiological functions. This, coupled with the historic pharmaceutical interest as well as growing concern over chemicals in the environment with the ability to behave like SERMs, has increased the demand for assays to detect SERM-like activity. Here, we describe a common, straightforward in vitro assay investigating the induction of classic ER-target genes in MCF7 breast cancer cells, allowing one to identify ligands with SERM-like activity.