The E3 ubiquitin ligase and tumor suppressor SCFFbw7 exists as three isoforms that govern the degradation of a host of critical cell regulators, including c-Myc, cyclin E, and PGC-1α. Peroxisome proliferator activated receptor-gamma coactivator 1α (PGC-1α) is a transcriptional coactivator with broad effects on cellular energy metabolism. Cellular PGC-1α levels are tightly controlled in a dynamic state by the balance of synthesis and rapid degradation via the ubiquitin-proteasome system. Isoform-specific functions of SCFFbw7 are yet to be determined. Here, we show that the E3 ubiquitin ligase, SCFFbw7, regulates cellular PGC-1α levels via two independent, isoform-specific, mechanisms. The cytoplasmic isoform (SCFFbw7β) reduces cellular PGC-1α levels via accelerated ubiquitin-proteasome degradation. In contrast, the nuclear isoform (SCFFbw7α) increases cellular PGC-1α levels and protein stability via inhibition of ubiquitin-proteasomal degradation. When nuclear Fbw7α proteins are redirected to the cytoplasm, cellular PGC-1α protein levels are reduced through accelerated ubiquitin-proteasomal degradation. We find that SCFFbw7β catalyzes high molecular weight PGC-1α-ubiquitin conjugation, whereas SCFFbw7α produces low molecular weight PGC-1α-ubiquitin conjugates that are not effective degradation signals. Thus, selective ubiquitination by specific Fbw7 isoforms represents a novel mechanism that tightly regulates cellular PGC-1α levels. Fbw7 isoforms mediate degradation of a host of regulatory proteins. The E3 ubiquitin ligase, Fbw7, mediates PGC-1α levels via selective isoform-specific ubiquitination. Fbw7β reduces cellular PGC-1α via ubiquitin-mediated degradation, whereas Fbw7α increases cellular PGC-1α via ubiquitin-mediated stabilization.