Poor cellular delivery and low bioavailability of novel potent therapeutic molecules continue to remain the bottleneck of modern cancer and gene therapy. Cell-penetrating peptides have provided immense opportunities for the intracellular delivery of bioactive cargos and have led to the first exciting successes in experimental therapy of muscular dystrophies. This review focuses on the mechanisms by which cell-penetrating peptides gain access to the cell interior and deliver cargos. Recent advances in augmenting delivery efficacy and facilitation of endosomal escape of cargo are presented, and the cell-penetrating peptide-mediated delivery of two of the most popular classes of cargo molecules, oligonucleotides and proteins, is analyzed. The arsenal of tools for oligonucleotide delivery has dramatically expanded in the last decade enabling harnessing of cell-surface receptors for targeted delivery.