LL-37 is one of the best-studied ↵-helical AMPs, and its potent antimicrobial activity and safety has been evaluated in clinical trials . Its therapeutic potential has driven the synthesis of various LL-37 derivatives. Studies on shorter fragments, such as the first 20 or 32 residues, revealed that residue R23 plays a crucial role in membrane anchoring, while the C-terminal region is essential for dimerization and deep insertion into the membrane . Truncation of the C-terminus causes a drastically changed action mode , with LL-37 forming toroidal pores, whereas LL-32 destabilizes membranes through a carpet-like mechanism. Figure illustrates that perfectly helical peptides, such as LL-32, do not form toroidal pores, highlighting the complexity of peptide structure-function relationships. Minor structural modifications can result in substantial changes in how a peptide interacts with bacterial membranes. Moreover, LL-37 and its derivatives have been demonstrated to posses a multi-factorial antimicrobial activity,including endotoxin neutralization and immune modulation roles. The endotoxin-neutralizing effect was demonstrated for the truncated version LL-32, leading to reduced TLR-4 signaling by inhibiting the TLR-4 activation pathway shown in Figure , and resulting in decreased TNF-↵ secretion . The anti-inflammatory activity of LL-32 was also attributed to its reorganizing activity on host cell membrane raft domains, reducing overall TLR-4 activation . Overall the studies regarding LL-37 and its close derivatives highlight the complexity of its mechanism of action and the challenges in reconstructing the SAR of a multi-factorial AMP.