In addition to proteasomes, lysosomes provide another independent pathway for the eukaryotic cells to degrade disease-related proteins. Recently, targeted protein degradation strategies via the lysosomal pathway have been explored that as well could degrade membrane proteins, extracellular proteins, and protein aggregates, thus greatly expanding the range of substrates for TPD. As a result of intensive research in the area, a number of new strategies via the lysosomal pathway, such as LYTAC, AbTAC, ATTEC, AUTAC, bispecific aptamer chimeras, and AUTOTAC have recently emerged. In the long run, structure-based rational optimization approaches for perfection of the targeted protein degraders are highly needed. Altogether, advanced knowledge of the precise mechanisms of the molecular glues operation, their structural biology, and medicinal chemistry features would be of utmost importance in transforming and progressing the targeted protein degradation strategy into favorable practical application in the clinic.