Retinoic acid (RA)-induced expression of bone morphogenetic protein-4 (BMP-4) inhibits in vitro and in vivo cell proliferation and ACTH synthesis in corticotroph-derived tumor cells. Reduced expression of BMP-4 in this adenoma subtype is associated with epigenomic silencing, and similar silencing mechanisms are also associated with the RA-responsive dopamine D2 receptor (D2R) in somatolactotroph cells. We now show that preincubation with the epidrugs zebularine and trichostatin A is obligate and permissive for RA-induced expression of the BMP-4 and the D2R genes in pituitary tumor cells. Combined epidrug challenges are associated with marginal reduction in CpG island methylation. However, significant change to histone tail modifications toward those associated with expression-competent genes is apparent, whereas RA challenge alone or in combined incubations does not have an impact on these modifications. Epidrug-mediated and RA-augmented expression of endogenous BMP-4 increased or decreased cell proliferation and colony-forming efficiency in GH3 and AtT-20 pituitary tumor cells, respectively, recapitulating recent reports of challenges of these cells with exogenous ligand. The specificity of the BMP-4-mediated effects was further supported by knock-down experiments of the BMP-4 antagonist noggin (small interfering RNA [siRNA]). Knock-down of noggin, in the absence and the presence of epidrugs, induced and augmented BMP-4 expression, respectively. In cell proliferation assays, challenge with either epidrugs or siRNA led to significant increase in cell numbers at the 72-hour time point; however, in siRNA-treated cells coincubated with epidrugs, a significant increase was apparent at the 48-hour time point. These studies show the potential of combined drug challenges as a treatment option, where epidrug renders silenced genes responsive to conventional therapeutic options.