The late 1990s through the 2000s shifted proteostasis research toward a unified, cross-compartment framework, showing that endoplasmic reticulum quality control and cytosolic surveillance are coupled within a single proteostasis network. Research revealed that sensing mechanisms trigger transcriptional programs which tune folding capacity and degrade misfolded substrates through the ubiquitin–proteasome system, linking secretory pathway integrity to cellular stress responses. Chaperone networks, including cytosolic Hsp70 cohorts, were demonstrated to direct misfolded proteins to degradation or refolding decisions, revealing how cofactor dynamics shape substrate fate across compartments. Historical Significance: This paradigm redefined proteostasis by integrating ER and cytosolic quality-control processes under common regulatory logic, positioning transcription factors such as ATF6α and XBP1 as central governance nodes. The discoveries established a foundational model for disease contexts where proteostasis fails and inspired therapeutic concepts that target both ER quality-control programs and cytosolic degradation pathways. By revealing cross-compartment coordination as essential for cellular homeostasis, the period set a long-lasting agenda for systems-level studies of proteostasis.