Mitochondria are key organelles with essential functions and fundamental roles in cell death and survival signaling. Consequently, they are involved in a wide range of diseases with a great diversity of clinical appearance, which makes them attractive as target for drugs to treat metabolic and degenerative diseases and cancer. Efficient methods for specific intracellular delivery of exogenous compounds, including biochemically active small molecules, imaging agents, peptides, peptide nucleic acids, proteins, RNA, DNA, and nanoparticles, would be beneficial for research and patients. A sustained effort in the last 20 years has been done to exploit cell-penetrating peptides (CPPs) for the delivery of such useful cargoes in vitro  and in vivo  because of their biocompatibility, ease of synthesis, and controllable physical chemistry. Here, we discuss the mechanisms by which CPPs can function, the use of this alternative as well as strategies used to target mitochondria and the implications for drug delivery.