, and are both common commensals and major opportunistic human pathogens. In recent decades, these bacteria have acquired broad resistance to several major classes of antibiotics, including commonly employed glycopeptides. Exemplified by resistance to vancomycin, glycopeptide resistance is mediated through intrinsic gene mutations, and/or transferrable resistance gene cassette-carrying mobile genetic elements. Here, this review will discuss the epidemiology of vancomycin-resistant and in healthcare, community, and agricultural settings, explore vancomycin resistance in the context of and non- mediated resistance development and provide insights into alternative therapeutic approaches aimed at treating drug-resistant and infections.