More than three decades of research have been necessary to understand the biological barriers that limit tissue-specific drug delivery and possible strategies to overcome them. Designing therapies with desired effectiveness but low toxicities still represents one of the major challenges in medicine. These endeavors have yielded various successes in developing targeting strategies applicable in both preclinical and clinical settings, encompassing small molecule, nucleic acid, peptide, antibody, and cell-based approaches. Most of the notable signs of progress and advancing theories in tissue-specific drug delivery are discussed below.