The ubiquitin-proteasome pathway has become an increasingly important regulatory mechanism for protein function. Countless proteins are degraded by the addition of polymeric ubiquitin chains, but more recently, monoubiquitination has emerged as a mechanism for regulatory functions other than proteasomal degradation. Monoubiquitination acts as a signal in nuclear export for the tumor suppressor protein p53. Different levels of Mdm2 are capable of inducing both mono- and polyubiquitination in a dosage dependent manner, thus determining p53's fate. Our findings demonstrate monoubiquitin-mediated protein trafficking can be expanded to nuclear-cytoplasmic shuttling, and also imply similar scenarios may apply to other cellular factors.