Wild-type promyelocytic leukemia (PML) protein and an increasingly documented number of cellular proteins are localized within discrete nuclear structures known as PML nuclear bodies or PODs (potential oncogenic domains). Even though POD function remains elusive, the integrity, topology, and molecular composition of these nuclear compartments have been associated with certain human diseases, including cancer, autoimmunity, neurodegenerative disorders, and viral propagation. At the molecular level, PML protein has been shown to be a coactivator of nuclear hormone receptors, whereas its oncogenic counterpart PML-retinoic acid receptor alpha, which promotes POD disaggregation, has been found to activate activator protein-1 transcription in a retinoic acid-dependent manner. Recently, we demonstrated that the CREB-binding protein (CBP) associates with PML protein in vitro and is recruited to the PODs in vivo in a signal-dependent manner. In exploring the consequence of this association, we proposed that POD nuclear bodies are regulatory cellular domains where proteins such as the CBP and CBP-interacting molecules may be activated or inactivated to coordinate signal-activated cellular response. This paper discusses the association of PML nuclear bodies with transcription control and underscores the pharmacological aspects of such an observation.