Metabolic dysfunction-associated steatotic liver disease (MASLD) presents a growing global health challenge requiring innovative approaches for effective management. This comprehensive review examines novel risk factors, including environmental pollutants like heavy metals, and underscores the complexity of personalized medicine tailored to individual patient profiles, influenced by gender and sex differences. Traditional treatments for MASLD, such as glucose- and lipid-lowering agents, show mixed results, highlighting the necessity for larger, long-term studies to establish safety and efficacy. Alternative therapies, including antioxidants, stem cells, and antiplatelets, although promising, demand extensive clinical trials for validation. This review highlights the importance of personalized medicine, considering individual variations and specific factors such as gender and sex, to optimize treatment responses. The shift from metabolic-associated fatty liver disease (MAFLD) to MASLD terminology underscores the metabolic components of the disease, aligning with the multiple-hit theory and highlighting the necessity for comprehensive risk factor management. Our vision advocates for an integrated approach to MASLD, encompassing extensive risk factor analysis and the development of safer, more effective treatments. Primary prevention and awareness initiatives are crucial in addressing the rising prevalence of MASLD. Future research must prioritize larger, long-term studies and personalized medicine principles to ensure the effective use of emerging therapies and technologies. The review underscores the need for continuous exploration and innovation, balancing the benefits and challenges of nanotechnology, to combat MASLD and improve patient outcomes comprehensively.