Delivery remains a key limitation to the use of oligonucleotide-based therapeutics. Uptake of oligonucleotides is limited by their high molecular weights and hydrophilicity, independent of whether the oligonucleotide works through siRNA, antisense or splice switching mechanisms. It is now known that siRNA and antisense molecules conjugated to GalNAc bind to and are internalized by the asialoglycoprotein receptor on hepatocytes, and recent data demonstrate receptor-mediated uptake increases the efficacy of the GalNAc-conjugated oligonucleotides up to 30-fold. Although there are multiple diseases of hepatocellular origin, effective delivery of oligonucleotides to a larger repertoire of cell types would enable oligonucleotide technologies to be applied more broadly and effectively across a range of diseases. Antibody-drug conjugates (ADCs) have been successfully developed using tumor-targeting monoclonal antibodies (mAbs) to deliver small molecule payloads of oncolytic drugs to tumor cells. Building on that knowledge and combining mAb targeting with siRNA and antisense technologies, we have generated antibody-oligonucleotide conjugates (AOCs). AOCs are stable and can circulate intact in plasma for days. The delivery of the oligonucleotide payload is driven by antibody binding to cell surface receptors, and thus it is possible to get cell-selective uptake. Using AOC technology, we have demonstrated reductions in target mRNA concentrations after systemic administration in cell types that include tumor, liver, muscle, heart and immune cells. Protein reduction, phenotypic changes and functional changes as well as RISC loading all correlate with mRNA knockdown. Selection of cell-specific antibodies, improved siRNA optimization and further advances in antibody technologies and linker strategies are extending the promise of the AOC as a platform.