The rapid expansion of the palm oil industry has generated vast quantities of palm oil mill effluent (POME) and associated waste, thereby posing significant environmental challenges. Although the industry contributes substantially to economic development, the large volume of POME—a liquid waste with high organic content—presents serious risks to aquatic ecosystems, soil quality, and natural processes when discharged untreated. Fresh POME is typically characterized by a viscous consistency, brownish color, unpleasant odor, acidic pH, and elevated levels of organic matter, as indicated by high chemical oxygen demand (COD) and biological oxygen demand (BOD). Moreover, its rich organic composition can promote biogas production, which in turn contributes to greenhouse gas emissions. Biological pretreatment has emerged as a promising and sustainable approach to address these challenges. This method exploits the natural degradative capabilities of diverse microbial communities—including bacteria, fungi, and algae—and their enzymes to effectively break down organic pollutants present in POME. Compared to traditional treatment methods, biotechnological approaches offer several advantages: they are environmentally compatible through the use of naturally occurring microorganisms, economically feasible due to lower operational costs and the potential for biogas recovery, and inherently safer by minimizing the risks associated with chemical handling and disposal. This chapter provides a comprehensive overview of biotechnological strategies for the sustainable treatment of POME, highlighting both the key benefits and the challenges associated with their implementation.