RUNX (AML/CBFA/PEBP2) transcription factors serve as paradigms for obligatory relationships between nuclear structure and physiological control of phenotypic gene expression. The RUNX proteins contribute to tissue restricted transcription by sequence-specific binding to promoter elements of target genes and serving as scaffolds for the assembly of coregulatory complexes that mediate biochemical and architectural control of activity. We will present an overview of approaches we are pursuing to address: (1) the involvement of RUNX proteins in governing competency for protein/DNA and protein/protein interactions at promoter regulatory sequences; (2) the recruitment of RUNX factors to subnuclear sites where the machinery for expression or repression of target genes is organized; and (3) the trafficking and integration of regulatory signals that control RUNX-mediated transcription.