Recently, targeted drug delivery systems (TDDSs) have been extensively studied as a promising therapeutic for tumor therapy. In this review, we investigate the typical targeting mechanisms of TDDSs, covering both passively and actively targeting DDSs for tumor therapy. We highlight the popular active targeting strategies for different sites of action, including tumor cytomembrane or various organelles. Finally, we present some recent representative TDDSs that are under testing in preclinical/clinical trials and have shown excellent clinical potential as the alternate treatment strategy for tumor therapy. Although TDDSs are proving to be promising therapeutic nanoplatforms for tumor therapy, extended investigations should be considered in the landscape for highly efficient tumor therapy with good biosafety.