The occurrence of drug-resistant bacteria is drastically rising and new and effective antibiotic classes are urgently needed. However, most of the compounds in development are minor modifications of previously used drugs to which bacteria can easily develop resistance. The investigation of inorganic and organometallic compounds as antibiotics is an alternative approach that holds great promises due to the ability of such molecules to trigger metal-specific mechanisms of action, which results in lethal consequences for pathogens. In this review, a selection of concepts to rationally design inorganic and organometallic antibiotics is discussed, highlighting their advantages by comparing them to classical drug discovery programmes. The review concludes with a short perspective for the future of antibiotic drug development and the role metal-based compounds will play in the field.