ABSTRACT Xylene, an aromatic hydrocarbon that exists as a colorless liquid or gas, is widely utilized across various industries. It serves multiple essential functions and is considered the gold standard in histopathological diagnostic procedures. However, its valuable properties are overshadowed by its toxic emissions, which pose significant health risks to laboratory personnel, particularly histopathology technicians. These hazards necessitate the immediate implementation of strict safety protocols during their handling. Due to the increasing awareness of these health risks, research into safer and more sustainable alternatives has expanded considerably. Various natural extracts and synthetic compounds have been explored, though only a few have demonstrated comparable efficacy to xylene. This review consolidates the findings from past decades, with special emphasis on agents that preserve diagnostic accuracy while offering enhanced biosafety, cost‐effectiveness, and suitability for routine use in histopathological laboratories.