Antimicrobial peptides (AMPs) are part of the innate immunity, aiding in the defense against pathogens. Cathelicidins represent a class of cationic AMPs distributed across various organisms, including mammals, birds, reptiles, amphibians, and fish. These peptides perform several important functions for the host, contributing to the direct elimination of pathogens by their microbicidal activities, while also promoting immune modulation, wound healing, and anti-tumor effects. Based on their versatility, cathelicidins have been investigated as therapeutic agents against infections, inflammatory and autoimmune diseases, and tumors. The present review summarizes the most recent discoveries regarding the use of cathelicidins in therapy, while addressing challenges such as cytotoxicity, production costs, and bacterial resistance. Additionally, combining nanomaterials with active, natural antimicrobial peptides, including LL-37 and synthetic analogs like ceragenins, leads to the creation of innovative nanoagents with significant clinical promise. Despite the vast number of pre-clinical studies, very few peptides have progressed to clinical trials. Nevertheless, the recent advances in nanomaterials and synthetic biology may help overcome the current limitations, enabling the use of cathelicidins in future therapeutics.