Myc and Mad family proteins regulate diverse biological processes through their capacity to influence gene expression directly. Their biochemical profiles, as well as their behaviour in surrogate assays for transcription and transformation, support a model in which the opposing properties of Myc and Mad occur primarily through their reciprocal regulation of common gene targets. An examination of this model on several levels reveals that Myc and Mad family basic regions are not functionally equivalent in oncogenesis, that their E box-binding activity is influenced by critical interactions between flanking nucleotide sequences and non-conserved residues at position 2 of the basic region, and that there is lack of complete concordance in the genes regulated by the Myc and Mxi1 basic regions. These data support the view that the opposing biological actions of Myc and Mxi1 are likely to extend beyond reciprocal regulation of common gene targets. This complex inter-relationship is further emphasized by the finding that alterations in the basic region can influence the ability of Myc to directly repress targets, suggesting that the basic region may also have a role in Inter-mediated gene regulation. Identification of these differentially regulated gene targets provides a framework for understanding the mechanism through which Myc governs the growth and survival of normal and neoplastic cells.