Thiazoles, their benzofused systems, and thiazolidinone derivatives are widely recognized as nuclei of great value for obtaining molecules with various biological activities, including analgesic, anti-inflammatory, anti-HIV, antidiabetic, antitumor, and antimicrobial. In particular, in the past decade, many compounds bearing these heterocycles have been studied for their promising antibacterial properties due to their action on different microbial targets. Here we assess the recent development of this class of compounds to address mechanisms underlying antibiotic resistance at both bacterial-cell and community levels (biofilms). We also explore the SAR and the prospective clinical application of thiazole and its benzofused derivatives, which act as inhibitors of mechanisms underlying antibiotic resistance in the treatment of severe drug-resistant infections. In addition, we examined all bacterial targets involved in their antimicrobial activity reporting, when described, their spontaneous frequencies of resistance.