MYC is an oncoprotein transcription factor that is overexpressed in the majority of malignancies. The oncogenic potential of MYC stems from its ability to bind regulatory sequences in thousands of target genes, which depends on interaction of MYC with its obligate partner, MAX. Here, we show that broad association of MYC with chromatin also depends on interaction with the WD40-repeat protein WDR5. MYC binds WDR5 via an evolutionarily conserved “MYC box IIIb” motif that engages a shallow, hydrophobic cleft on the surface of WDR5. Structure-guided mutations in MYC that disrupt interaction with WDR5 attenuate binding of MYC at ∼80% of its chromosomal locations and disable its ability to promote induced pluripotent stem cell formation and drive tumorigenesis. Our data reveal WDR5 as a key determinant for MYC recruitment to chromatin and uncover a tractable target for the discovery of anticancer therapies against MYC-driven tumors. Display omitted •MYC binds directly to the prevalent chromatin regulator WDR5•Interaction with WDR5 is broadly required for MYC to bind chromatin•Mutations that disrupt WDR5 binding perturb MYC-driven cancer and iPSC formation•Properties of the MYC–WDR5 interface make it amenable to small molecule inhibition MYC is an oncoprotein transcription factor that features prominently in human cancer. Thomas et al. demonstrate that recruitment of MYC to chromatin—and its ability to function as an oncoprotein—depends on its direct interaction with the WD40-repeat protein WDR5.