Methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA) have emerged as a global health concern. A new class of compounds featuring an aryl isonitrile moiety has been discovered that exhibits potent inhibitory activity against several clinically-relevant MRSA and VRSA isolates. Structure-activity relationship studies have been conducted to identify the aryl isonitrile group as the key functional group responsible for the observed antibacterial activity. The most potent antibacterial aryl isonitrile analogs (MIC 2 μM) did not show any toxicity against mammalian cells up to a concentration of 64 μM.