Inducing changes in the levels of the MYC oncoprotein is shown to activate and repress specific sets of target genes that are characteristic of tumour cells, providing an insight into the mechanism by which MYC can stimulate tumorigenesis in contrast to its physiological role. The mammalian Myc oncoprotein is a transcription factor that binds to thousands of promoters. Two current models for Myc function propose that it is either a gene-specific regulator of transcription, or a global amplifier of all active genes. Two groups reporting in this issue of Nature present evidence in support of the idea that Myc regulates specific genes. Arianna Sabò et al. analyse Myc genomic distribution and RNA expression profiles during B-cell lymphomagenesis in mice and Susanne Walz et al. compare normal cells and Myc-transformed tumour cells. Although both groups find that Myc overexpression can result in a general increase in gene expression, the effect is an indirect one. Modulated by various other transcription factors, Myc seems to act primarily by regulating specific groups of genes. In mammalian cells, the MYC oncoprotein binds to thousands of promoters1,2,3,4. During mitogenic stimulation of primary lymphocytes, MYC promotes an increase in the expression of virtually all genes1. In contrast, MYC-driven tumour cells differ from normal cells in the expression of specific sets of up- and downregulated genes that have considerable prognostic value5,6,7. To understand this discrepancy, we studied the consequences of inducible expression and depletion of MYC in human cells and murine tumour models. Changes in MYC levels activate and repress specific sets of direct target genes that are characteristic of MYC-transformed tumour cells. Three factors account for this specificity. First, the magnitude of response parallels the change in occupancy by MYC at each promoter. Functionally distinct classes of target genes differ in the E-box sequence bound by MYC, suggesting that different cellular responses to physiological and oncogenic MYC levels are controlled by promoter affinity. Second, MYC both positively and negatively affects transcription initiation independent of its effect on transcriptional elongation8. Third, complex formation with MIZ1 (also known as ZBTB17)9 mediates repression of multiple target genes by MYC and the ratio of MYC and MIZ1 bound to each promoter correlates with the direction of response.