...These prodrugs are generally designed via modification of senolytics with a cleavable galactose moiety to respond to the senescent biomarker - senescence-associated β-galactosidase (SA-β-gal) to restore their therapeutic effects. In this Concept, we summarize the developments by categorizing these prodrugs into two classes: 1) galactose-modified senolytic prodrugs, in which sensing unit galactose is either directly conjugated to the drug or via a self-immolative linker and 2) bioorthogonal activation of senolytic prodrugs. In the bioorthogonal prodrug design, galactose is incorporated into dihydrotetrazine to sense SA-β-gal for click activation. Notably, in addition to repurposed chemotherapeutics and small molecule inhibitors, PROTACs and photodynamic therapy have been introduced as new senolytics in the prodrug design. It is expected that the senolytic prodrugs would facilitate translating small-molecule senolytics into clinical use.