Significance: Lung diseases are on the second rank worldwide with respect to morbidity and mortality. For most respiratory diseases no effective therapies exist. While the proteasome has been successfully evaluated as a novel target for therapeutic interventions in cancer, neurodegenerative, and cardiac disorders, there is a profound lack of knowledge on the regulation of proteasome activity in chronic and acute lung diseases. Recent advances have identified various means of how the amount of active proteasome complexes in the cell can be regulated such as transcriptional regulation of proteasomal subunit expression, association with different regulators, assembly and half-life of proteasomes and regulatory complexes, as well as posttranscriptional modifications. It also becomes increasingly evident that proteasome activity is fine-tuned and depends on the state of the cell. We propose here that 20S proteasomes and their regulators can be regarded as dynamic building blocks, which assemble or disassemble in response to cellular needs. The composition of proteasome complexes in a cell may vary depending on tissue, cell type and compartment, stage of development, or pathological context. Critical Issues and Future Directions: Dissecting the expression and regulation of the various catalytic forms of 20S proteasomes, such as constitutive, immuno-, and mixed proteasomes, together with their associated regulatory complexes will not only greatly enhance our understanding of proteasome function in lung pathogenesis but will also pave the way to develop new classes of drugs that inhibit or activate proteasome function in a defined setting for treatment of lung diseases.