Lipopeptide daptomycin is one of the few recently approved antibiotics based on the novel mechanism of action. Recent advances in synthetic lipopeptides, driven by the biochemical and biophysical research, expanded their spectrum of antimicrobial activity and reduced their size to achieve economically viable production. Lipopeptides, consisting of a short peptide chain conjugated with an acyl chain, form a structurally defined conformation, which inserts into the bacterial membrane and dissipates its transmembrane potential. In addition to antimicrobial activity, synthetic lipopeptides also suppress inflammation through the neutralization of bacterial agonists of the innate immune response, synergize with conventional antibiotics and have improved proteolytic stability. Activities in animal models indicate that synthetic lipopeptides may surpass the natural lipopeptides as the perspective class of anti-infective agents.