Therapeutic applications of antisense oligonucleotides (ASOs) will be expanded by methods that direct ASO uptake into targeted cell types and deliver the ASO to desired subcellular locations. With this objective, we have applied novel peptidic molecular guidance systems (MGSs) to facilitate cell-specific ASO delivery. These MGSs have the unique ability to bind to specific epithelial-derived cancer cell types and, upon binding, trigger rapid internalization and trafficking to specific subcellular locations. The chemically optimized MGSs have 1-10 nM affinities for their cellular targets, serum stability greater than 48 hours, and 50-1000-fold specificity for targeted cancer cells over normal control cells. Target cells internalize these peptidic ligands rapidly, reaching intracellular concentrations up to 1.5 µM with t[1/2] of 10-30 minutes. Conjugates of stabilized ASOs with these MGSs show robust, temperature-dependent uptake into human lung cancer cells, observed with flow cytometry and fluorescence microscopy. Cell-type specificity for conjugate internalization confirms MGS specificity. Furthermore, MGS-mediated delivery enhances ASO potency: conjugation of an MGS to a Generation 2.5 ASO targeting MALAT-1 increases ASO potency in the targeted cancer cells by up to seven-fold compared to the unconjugated ASO. Conversely, antisense activity of the conjugated ASO is markedly reduced in cells not targeted by the MGS. These results demonstrate a strategy for cell-specific delivery of ASOs as the cargo of engineered cell-targeting peptides.