This mini review covers the drug discovery aspect of both proteasome activators and inhibitors. The proteasome is involved in many essential cellular functions, such as regulation of cell cycle, cell differentiation, signal transduction pathways, antigen processing for appropriate immune responses, stress signaling, inflammatory responses, and apoptosis. Due to the importance of the proteasome in cellular functions, inhibition or activation of the proteasome could become a useful therapeutic strategy for a variety of diseases. Many proteasome inhibitors have been identified and can be classified into two groups according to their source: chemically synthesized small molecules and compounds derived from natural products. A successful example of development of a proteasome inhibitor as a clinically useful drug is the peptide boronate, PS341 (Bortezomib), was approved for the treatment of multiple myeloma. In contrast to proteasome inhibitors, small molecules that can activate or enhance proteasome activity are rare and are not well studied. The fact that over-expression of the cellular proteasome activator PA28 exhibited beneficial effects on the Huntington's disease neuronal model cells raised the prospect that small molecule proteasome activators could become useful therapeutics. The beneficial effect of oleuropein, a small molecule proteasome activator, on senescence of human fibroblasts also suggested that proteasome activators might have the potential to be developed into anti-aging agents.