Although Paul Ehrlich has envisioned the concept of targeted delivery of a cytotoxic agent to cancer cells back to 1913, the clinical efficacy of anticancer agents has been limited due to poor solubility, lack of selectivity, unmanageable off-target toxicities, and the emergence of multidrug resistance. Combination of active tumor targeting and covalent attachment of drug molecules to carriers such as proteins, peptides, carbohydrates, polymers, and nanoparticles has shown great potential in enhancing solubility, selectivity, and therapeutic index. However, producing homogeneous drug products has been difficult due to a lack of orthogonal conjugation chemistries that combines covalent drug attachment with targeted delivery on a single platform. To address these limitations, in first approach we describe a multifunctional gold nanoparticle decorated with hydrazine, amine, or dibenzocyclooctynol for sequential conjugation of doxorubicin through an acid-labile hydrazone linkage, an imaging agent through an amide bond, and a glycan-based ligand for the cell surface receptor CD22 of B-cells using SPAAC showing excellent conjugation efficiencies. In the second approach, an orthogonal glycoengineering strategy that allows sequential site-specific conjugation of dual-drug to anti-CD22 antibody was described. This method relies on an observation that sialyltransferase (ST6Gal1) has a preference for the ?1,3-Man-?1,2-GlcNAc-?1,4-Gal bottom arm of the glycan of IgG over top arm. This unique feature has enabled the sequential introduction of reactive functional groups that in turn can undergo SPAAC with FDA approved anticancer agent such as paclitaxel and zosuquidar, potent P-glycoprotein modulator currently under phase-III clinical trials for the treatment of acute myeloid leukemia. The resulting anti-CD22 antibody showed superior anti-cancer activities and can bypass multidrug resistance in lymphoma cancer cells. Payloads that overcome multidrug resistance are highly desired for ADCs. A novel paclitaxel scaffold with 2-methylpropenyl at C3' and (E)-6-((tert-butoxycarbonyl)amino) hexenoic acid modification at C3'-N-acyl position has been synthesized. The dual modification furnished highly potent analogs against multidrug-resistance cancer cells and has enabled flexibility of introducing various clickable groups or stable yet cleavable linkers.