Natural products have historically been a rich source of diverse chemical matter with numerous biological activities, and have played an important role in drug discovery in many areas including infectious disease. Synthetic and medicinal chemistry have been, and continue to be, important tools to realize the potential of natural products as therapeutics and as chemical probes. The formation of biofilms by bacteria in an infection setting is a significant factor in the recalcitrance of many bacterial infections, conferring increased tolerance to many antibiotics and to the host immune response, and as yet there are no approved therapeutics for combatting biofilm-based bacterial infections. Small molecules that interfere with the ability of bacteria to form and maintain biofilms can overcome antibiotic tolerance conferred by the biofilm phenotype, and have the potential to form combination therapies with conventional antibiotics. Many natural products with anti-biofilm activity have been identified from plants, microbes, and marine life, including: elligic acid glycosides, hamamelitannin, carolacton, skyllamycins, promysalin, phenazines, bromoageliferin, flustramine C, meridianin D, and brominated furanones. Total synthesis and medicinal chemistry programs have facilitated structure confirmation, identification of critical structural motifs, better understanding of mechanistic pathways, and the development of more potent, more accessible, or more pharmacologically favorable derivatives of anti-biofilm natural products.