The scope and extent of molecular cytopathology in the era of precision medicine has been expanding in recent years. The versatility of cytology specimen preparations has provided ample opportunity for the cytopathology community to evolve, innovate and ‘do more with less’ using limited amounts of tissue. More recently, cytology-derived supernatant liquid biopsy samples have been identified as a substantial source of high-quality genomic material that can be interrogated for genotyping for therapeutic decision-making, as well as other roles in cancer screening for early-stage disease, longitudinal monitoring for therapeutic response and disease prognostication. These novel substrates, including supernatants from body fluids such as urine, pleural effusion, ascitic fluid, cerebrospinal fluid, as well as fine-needle aspiration (FNA) specimens, serve as a bridge between tissue-based testing and conventional liquid biopsy testing from the patient's plasma. Cytologically derived liquid biopsy samples can only be used in situations where the tissue sample is inadequate for genotyping, or when plasma-based liquid biopsy fails to identify an oncogenic driver alteration, but they can be used as a stand-alone complementary specimen source that can provide reliable genomic information for therapeutic decisions. This review aims to highlight some of the advances in the field and the clinical applications of the cytology-derived supernatant specimen.