The adherence of pathogenic microorganisms to surfaces and their association to form antibiotic-resistant biofilms threatens public health and affects several industrial sectors with significant economic losses. For this reason, the medical, pharmaceutical and materials science communities are exploring more effective anti-fouling approaches. This review focuses on the anti-fouling properties, structure–activity relationships and environmental toxicity of quaternary ammonium salts (QAS) and, as a subclass, ionic liquid compounds. Greener alternatives such as QAS-based antimicrobial polymers with biocide release, non-fouling (i.e., PEG, zwitterions), fouling release (i.e., poly(dimethylsiloxanes), fluorocarbon) and contact killing properties are highlighted. We also report on dual-functional polymers and stimuli-responsive materials. Given the economic and environmental impacts of biofilms in submerged surfaces, we emphasize the importance of less explored QAS-based anti-fouling approaches in the marine industry and in developing efficient membranes for water treatment systems.