Peroxisomal import function is often compromised under stress and aging, as demonstrated in recent studies from our group and others. Although it has become more and more appreciated that defective peroxisomal import contributes significantly to the loss of cellular homeostasis and aging, little is known about how cells mount defense mechanisms to maintain cellular and metabolic function during peroxisomal import stress. Recently, we have applied genomic (RNA-Seq) and genetic approaches (CRISPR screening) to comprehensively characterize and uncover cellular stress responses to defective peroxisomal protein import. In addition, we have begun to explore the role of peroxisome-mitochondrion communication in tissue aging, given that inter-organelle communication plays an essential role in maintaining cellular homeostasis.