The cyclic lipopeptides comprise a number of clinically relevant classes of antibiotics that date back from the discovery of the polymyxins in 1947 to the recent introduction of the semi-synthetic lipoglycopeptides. These natural products and natural product derivatives most often originate from soil-inhabiting and/or plant-derived producing organisms. The cyclic lipopeptides consist of peptide macrocycles that are acylated with a fatty acid lipid, and show great structural diversity owing to their nearly exclusive non-ribosomal synthesis production and/or post-translational modification. This review presents a summary of the main classes of cyclic lipopeptide antibiotics with regard to their characteristic structural features, modes of action, clinical relevance, and the onset of bacterial resistance.