Transcription-modulating drugs achieve their therapeutic effects through the modulation of gene transcription. To understand how selectivity is achieved, four groups of such drugs - including immunosuppressants, estrogen analogs, the antidiabetic thiazolidinediones, and the anti-inflammatory salicylates - will be discussed. The immunosuppressants cyclosporin A and FK506, when complexed with immunophilins, inactivate the protein phosphatase calcineurin, resulting in the inhibition of interleukin-2 gene activation. Another immunosuppressant, rapamycin, binds to the same immunophilin as FK506 but inactivates a protein kinase p70(s6k). Estrogen analogs tamoxifen and rolaxifene antagonize one estrogen receptor transactivation function (AF-2) and agonize another (AF-1). They modulate expression of a wide variety of genes, including transforming growth factor-alpha, insulin-like growth factor-1, and transforming growth factor-beta3, which are important for breast and endometrial cancer proliferation and bone maintenance respectively. The antidiabetic drugs thiazolidinediones bind and activate peroxisome proliferator-activated receptor gamma and suppress insulin resistance mediated by tumor necrosis factor-alpha. Salicylates inhibit transcription factor NFkappaB, which is important for immune and inflammatory responses. Continuing understanding of molecular mechanisms of such drugs not only helps to identify better drugs for these targets but should also provide an insight into developing future transcription-modulating drugs with better selectivity and reduced toxicity.