The human tumor suppressor Fbw7/hCdc4 functions as a phosphoepitope-specific substrate recognition component of SCF ubiquitin ligases [1] that catalyzes the ubiquitination of cyclin E [2–5], Notch [6, 7], c-Jun [8] and c-Myc [9–10]. Fbw7 loss in cancer may thus have profound effects on the pathways that govern cell division, differentiation, apoptosis, and cell growth. Fbw7-inactivating mutations occur in human tumor cell lines [2–4] and primary cancers [11–13], and Fbw7 loss in cultured cells causes genetic instability [13]. In mice, deletion of Fbw7 leads to embryonic lethality associated with defective Notch and cyclin E regulation [14, 15]. The human Fbw7 locus encodes three protein isoforms (Fbw7α, Fbw7β, and Fbw7γ) [2–4, 11]. We find that these isoforms occupy discrete subcellular compartments and have identified cis-acting localization signals within each isoform. Surprisingly, the Fbw7γ isoform is nucleolar, colocalizes with c-Myc when the proteasome is inhibited, and regulates nucleolar c-Myc accumulation. Moreover, we find that knockdown of Fbw7 increases cell size consistent with its ability to control c-Myc levels in the nucleolus. We suggest that interactions between c-Myc and Fbw7γ within the nucleolus regulate c-Myc's growth-promoting function and that c-Myc activation is likely to be an important oncogenic consequence of Fbw7 loss in cancers.