Besides their well-known function in cellular bioenergetics, the role of mitochondria in signaling regulation of cells homeostasis and survival has been uncovered during the past few decades. Possessing an independent genome and a unique genetic code, mitochondria biosynthesize protective stress response factors, the "mitochondrial-derived peptides," import and deposit peptides within their matrix and are the target of peptides bound to bioactive agents, aiming at alleviation of pathology-related malfunction of the electron transport chain. As the rapidly evolving field of mitochondrial peptides is appropriate for therapeutic exploitation, a brief overview of the major recent findings is timely needed. Here, the focus is on the following issues: (i) the biological effects of mitochondrial-derived peptides (humanin, humanin-like peptides and MOTS-c) and their use in therapy, (ii) the abnormal accumulation of β-amyloid peptide within the mitochondrial matrix and (iii) the effectiveness of "mitochondrial cell-penetrating/targeting peptides" as vehicles for delivery of bioactive agents into dysfunctional mitochondria.