This review discusses the mechanisms of colistin resistance in Acinetobacter baumannii and available treatment strategies. A. baumannii is a major cause of nosocomial infections and has developed resistance to multiple antibiotics, including colistin, a last-resort treatment. Resistance mechanisms include modifications to lipopolysaccharide (LPS) structures, such as the addition of phosphoethanolamine (PEtN) or galactosamine to lipid A, which reduces colistin binding. Mutations in LPS biosynthesis genes like lpxA, lpxC, and lpxD also lead to LPS loss or modification, reducing colistin susceptibility. Additionally, alterations in outer membrane permeability, such as reduced expression of porins, contribute to resistance. Heteroresistance, where a small fraction of bacterial cells are resistant, is another factor. Available treatments for colistin-resistant A. baumannii include new antibiotics like cefiderocol and sulbactam/durlobactam, as well as combinations of antibiotics such as polymyxins, ampicillin/sulbactam, carbapenems, fosfomycin, tigecycline/minocycline, rifamycins, and aminoglycosides. While most studied combinations are polymyxin-based, non-polymyxin-based combinations are emerging as promising options. However, clinical data remain limited, and further research is needed to determine the optimal treatment strategies. Sulbactam-based regimens, such as ampicillin/sulbactam or sulbactam/durlobactam, are currently recommended for treatment. Despite the availability of new antibiotics, colistin resistance remains a significant challenge, and synergistic combinations are often the only viable option. The review emphasizes the need for continued investigation to develop more effective treatments for colistin-resistant A. baumannii infections.This review discusses the mechanisms of colistin resistance in Acinetobacter baumannii and available treatment strategies. A. baumannii is a major cause of nosocomial infections and has developed resistance to multiple antibiotics, including colistin, a last-resort treatment. Resistance mechanisms include modifications to lipopolysaccharide (LPS) structures, such as the addition of phosphoethanolamine (PEtN) or galactosamine to lipid A, which reduces colistin binding. Mutations in LPS biosynthesis genes like lpxA, lpxC, and lpxD also lead to LPS loss or modification, reducing colistin susceptibility. Additionally, alterations in outer membrane permeability, such as reduced expression of porins, contribute to resistance. Heteroresistance, where a small fraction of bacterial cells are resistant, is another factor. Available treatments for colistin-resistant A. baumannii include new antibiotics like cefiderocol and sulbactam/durlobactam, as well as combinations of antibiotics such as polymyxins, ampicillin/sulbactam, carbapenems, fosfomycin, tigecycline/minocycline, rifamycins, and aminoglycosides. While most studied combinations are polymyxin-based, non-polymyxin-based combinations are emerging as promising options. However, clinical data remain limited, and further research is needed to determine the optimal treatment strategies. Sulbactam-based regimens, such as ampicillin/sulbactam or sulbactam/durlobactam, are currently recommended for treatment. Despite the availability of new antibiotics, colistin resistance remains a significant challenge, and synergistic combinations are often the only viable option. The review emphasizes the need for continued investigation to develop more effective treatments for colistin-resistant A. baumannii infections.