The problem of aminoglycoside-induced ototoxicity, which was recognized within a year of the discovery of streptomycin to combat tuberculosis in 1944, is still of great concern due to the widespread use of these powerful antibacterial agents. These drugs can damage to varying degrees the cochlea and vestibular system. Their primary targets are the cochlear outer hair cells and the type I vestibular hair cells, which may lead to ataxia and/or hearing loss (beginning at high frequencies). Oxidative stress (reactive oxygen species [ROS]) has been implicated by several lines of evidence as a causative factor in aminoglycoside-induced hearing loss. The resulting imbalance of cellular redox-homeostasis then triggers redox-regulated signaling pathways, leading either to cell survival or cell death. Consistent with the idea that ROS are causally involved in aminoglycoside toxicity, both the morphological and physiological effects of the drugs can be prevented by antioxidants. In this article, we will discuss the general pathological and pathophysiological changes following aminoglycoside administration. We will also examine the underlying molecular pathology and consider free radical mechanisms and the activation of redox-regulated signal transduction pathways.