Oncogenic activation of genes that regulate cell proliferation and survival plays a central role in the development of human cancer. This activation is frequently achieved by the aberrant expression of oncogene products due to the gene amplification, enhanced transcription or stabilization of their mRNA or protein. The ubiquitin-proteasome pathway(UPP) is the key player in the intracellular degradation of regulatory proteins in eukaryotes. UPP controls the abundance and activity of important protein regulators of cellular signal transduction including a variety of cellular proto-oncogenes. Alteration of ubiquitination and degradation of these proto-oncogene proteins often occurs during tumorigenesis and critically contributes to cell decisions as per proliferation/differentiation and survival/death. This article attempts to briefly overview the role of UPP in the regulation of several signal transduction pathways that contribute to development of cancer.