Curcumin, a major component of the golden spice turmeric (Curcuma longa), has been linked with the prevention and treatment of a wide variety of cancers through modulation of multiple cell signaling pathways. Since the first report from our laboratory in 1995 that curcumin can inhibit activation of the proinflammatory transcription factor NF-κB by inhibiting the 26S proteasomal degradation of IκBα, an inhibitor of NF-κB, this yellow pigment has been shown to inhibit the protease activities of the proteasome. The carbonyl carbons of the curcumin molecule directly interact with the hydroxyl group of the amino-terminal threonine residue of the proteasomal CT-L subunit of 20S proteasome and cellular 26S proteasome. Curcumin is also a potent inhibitor of COP9 signalosome and associated kinases, casein kinase 2 and protein kinase D, all linked to the ubiquitin-proteasomal system (UPS). Curcumin can also directly inhibit ubiquitin isopeptidases, a family of deubiquitinases (DUBs) that salvage ubiquitin for reuse by the 26S proteasome system. The inhibition of this enzyme by curcumin is mediated through α,β-unsaturated ketone and two sterically accessible β-carbons. Regulation of the UPS pathway by curcumin has been linked to regulation of cancer-linked inflammatory proteins (such as COX-2 and iNOS), transcription factors (NF-κB, STAT3, Sp, AP-1, GADD153/CHOP, HIF-1α), growth factors (VEGF, HER2), apoptotic proteins (p53, Bcl-2, survivin, DNA topoisomerase II, HDAC2, p300, hTERT) and cell cycle proteins (cyclin D1, cyclin E, cyclin B, p21, p27) associated with the prevention and therapy of cancer. Interestingly, the effect of curcumin on 26S proteasome appears to be dose-dependent, as low doses (≥1 μM) increase proteasome activity whereas high doses (≤10 μM) inhibit the proteasome activity. In this review, we discuss in detail how modulation of these targets by curcumin is linked to prevention and treatment of cancer.