During the last 30 years, investigation of the transcriptional and translational mechanisms of gene regulation has been a major focus of molecular cancer biology. More recently, it has become evident that cancer-related mutations and cancer-related therapies also can affect post-translational processing of cellular proteins and that control exerted at this level can be critical in defining both the cancer phenotype and the response to therapeutic intervention. One post-translational mechanism that is receiving considerable attention is degradation of intracellular proteins through the multicatalytic 26S proteasome. This follows growing recognition of the fact that protein degradation is a well-regulated and selective process that can differentially control intracellular protein expression levels. The proteasome is responsible for the degradation of all short-lived proteins and 70-90% of all long-lived proteins, thereby regulating signal transduction through pathways involving factors such as AP1 and NFKB, and processes such as cell cycle progression and arrest, DNA transcription, DNA repair/misrepair, angiogenesis, apoptosis/survival, growth and development, and inflammation and immunity, as well as muscle wasting (e.g. in cachexia and sepsis). In this review, we discuss the potential involvement of the proteasome in both cancer biology and cancer treatment.