The lipid components of pathogen cell membranes have been considered as a poor pharmacological target, due to their universal distribution and apparent homogeneity throughout living organisms. Among the rare exceptions to this view one could mention polyene antibiotics such as amphotericin, or peptide antibiotics such as the polymyxins and the gramicidins. In the last two decades, however, the above notion has been challenged by two main lines of discovery; first, natural antimicrobial peptides (AMPs) that kill pathogens by interaction with phospholipids and membrane permeabilization, and secondly, cell-penetrating peptides (CPPs), capable of introducing into cells a variety of cargoes in the absence of specific receptors, again by interaction at some point with membrane phospholipids. For both AMPs and CPPs, the pharmacological proof-of-concept has been successfully demonstrated, and promising applications as nanobiotechnological tools have been envisaged though not hitherto materialized in clinical settings. In this review we briefly examine the pros and cons of these two classes of therapeutic agents, as well as strategies aimed at rationalizing and expanding their potentiality

Work supported by the European Union (HEALTH-2007-223414, Leishdrug, to L.R. and D.A.), the Fondo de Investigaciones Sanitarias (PI061125, PS09/01928 and RETICS-FEDER RD 06/0021/0006 to L.R.), the regional governments of Madrid (S-BIO-0260/2006 to L.R) and Catalonia (2009 SGR 492 to D.A.), and the Spanish Ministry of Science and Innovation (PET2006-0139 to L.R. and D.A.).