Acinetobacter baumannii has emerged as a significant challenge in clinical practice due to its resistance to multiple antibiotics, including colistin, a last-resort treatment. This review highlights the various mechanisms of colistin resistance in A. baumannii, such as modifications to lipopolysaccharide (LPS) structures, alterations in outer membrane permeability via porins, and heteroresistance. The review also evaluates available treatment options, including new antibiotics like cefiderocol and sulbactam/durlobactam, as well as various combinations of antibiotics. While colistin remains a crucial component in combination regimens, the effectiveness of these regimens is limited by the emergence of pan-drug-resistant (PDR) strains. The review emphasizes the need for continued research to determine optimal therapeutic strategies against colistin-resistant A. baumannii infections.Acinetobacter baumannii has emerged as a significant challenge in clinical practice due to its resistance to multiple antibiotics, including colistin, a last-resort treatment. This review highlights the various mechanisms of colistin resistance in A. baumannii, such as modifications to lipopolysaccharide (LPS) structures, alterations in outer membrane permeability via porins, and heteroresistance. The review also evaluates available treatment options, including new antibiotics like cefiderocol and sulbactam/durlobactam, as well as various combinations of antibiotics. While colistin remains a crucial component in combination regimens, the effectiveness of these regimens is limited by the emergence of pan-drug-resistant (PDR) strains. The review emphasizes the need for continued research to determine optimal therapeutic strategies against colistin-resistant A. baumannii infections.