This Viewpoint addresses the question of whether, after years of declining use, the time is ripe for renewed investigations into the aminoglycoside class of antibiotics for the development of novel therapeutic agents for the treatment of drug-resistant bacterial infections, particularly of the Gram-negative type. The reasons underlying the decline in use of the aminoglycosides are briefly considered and found to be outweighed by the ever-increasing clinical need for improved antibacterials with which to combat modern day multidrug resistant pathogens. The potential of the aminoglycosides builds on their well-established pharmacokinetics/pharmacodynamics (PK/PD), mechanisms of action, toxicity, and resistance and the extensive existing structure–activity relationship (SAR) databases, which permit rational, informed drug design. When coupled with the power of modern synthetic organic chemistry and improved funding scenarios, these multiple attributes open the door for the development of structurally novel, potent, and less toxic aminoglycosides to address the pressing societal problem of multidrug-resistant (MDR) infectious disease.