Proteasomes are multienzyme complexes that maintain protein homeostasis (proteostasis) and important cellular functions through the degradation of misfolded, redundant, and damaged proteins. It is well established that aging is associated with the accumulation of damaged and misfolded proteins. This phenomenon is paralleled by declined proteasome activity. When the accumulation of redundant proteins exceed degradation, undesirable signaling and/or aggregation occurs and are the hallmarks of neurodegenerative diseases and many cancers. Thus, increasing proteasome activity has been recognized as a new approach to delay the onset or ameliorate the symptoms of neurodegenerative and other proteotoxic disorders. Enhancement of proteasome activity has many therapeutic potentials but is still a relatively unexplored field. In this perspective, we review current approaches, genetic manipulation, posttranslational modification, and small molecule proteasome agonists used to increase proteasome activity, challenges facing the field, and applications beyond aging and neurodegenerative diseases.