Targeted protein degradation (TPD) allows targeting undruggable proteins for therapeutic applications as well as eliminating proteins of interest for research purposes. While several types of degraders that harness the proteasome or the lysosome have been developed, a technology that simultaneously degrades targets and accelerates cellular autophagic flux remains unavailable. In this lecture, I will introduce a TPD platform termed AUTOTAC (AUTOphagy-TArgeting Chimera), by which a broad range of cellular proteins can be selectively recognized and targeted to autophagic membranes for lysosomal degradation. Central to the mode of action in AUTOTAC is conformational and biological activation of otherwise inactive, archetypal autophagy cargo receptor p62/SQSTM1 into an autophagy-compatible form. This platform technology employs a bifunctional molecule composed of a target-binding ligand (TBL) linked to an autophagy-targeting ligand (ATL). AUTOTAC simultaneously binds targets via its TBL and the ZZ domain of the otherwise inactive autophagy receptor p62 via its ATL, which activates p62 in complex with targets into an autophagy-compatible form. Targets are biologically inactivated and sequestered by autophagosomes, leading to lysosomal degradation. AUTOTAC compounds were successfully used to degrade oncoproteins (androgen receptor, ras, estrogen receptor beta, and methionine aminopeptidase 2) and degradation-resistant aggregates in neurodegeneration, some of which exhibited sub-nanomolar DC50 values. ATB2005A, designed to target oligomeric tau species but not its monomers, showed DC50 of low nM in cultured cells and exerted therapeutic efficacy in mouse models of Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP) at 1 mg/kg oral adminstration. In GLP toxicity studies, ATB2005A showed NOAEL of 500 mg/kg in beagle dogs upon oral adminisratin three times per week over 4 weeks. Phase 1 clinical trials with 76 healthy volunteers are being conducted at Seoul National University Hospital to validate the safety and pharmacokinetics of ATB2005A. As a veterinary medicine, ATB2005A completed Phase 2 clinical trials in Slovevia, EU, with 33 companion dogs carrying canine cognitive dysfunction (CCD), a equivalent to human AD. Oral adminstration of ATB2005A for 6 weeks with 18 doses demonstrated disease-modifying therapeutic efficacy, which sustained at least 5 months afterwards.