This systematic review identifies and summarizes definitions of polypharmacy in existing literature. Polypharmacy refers to the use of multiple medications, which is common in older adults with multimorbidity. However, there is no consensus on a single definition. The review found 138 definitions, with 111 being numerical (based on the number of medications), 15 incorporating duration of therapy or healthcare setting, and 12 descriptive. The most common numerical definition is five or more medications daily, used by 46.4% of studies. Only 6.4% of articles distinguished between appropriate and inappropriate polypharmacy. Numerical definitions do not account for specific comorbidities and make it difficult to assess therapy safety and appropriateness in clinical settings. The review highlights the need for a more comprehensive and context-specific definition of polypharmacy to improve clinical decision-making and patient outcomes. The results suggest a shift towards using the term 'appropriate polypharmacy' to differentiate between prescribing 'many' and 'too many' drugs. The study emphasizes the importance of considering comorbidities and medication interactions when assessing polypharmacy. The review also notes the limitations of current tools and criteria used to identify inappropriate polypharmacy. Overall, the findings indicate a need for a more nuanced and evidence-based approach to defining and managing polypharmacy in clinical practice.This systematic review identifies and summarizes definitions of polypharmacy in existing literature. Polypharmacy refers to the use of multiple medications, which is common in older adults with multimorbidity. However, there is no consensus on a single definition. The review found 138 definitions, with 111 being numerical (based on the number of medications), 15 incorporating duration of therapy or healthcare setting, and 12 descriptive. The most common numerical definition is five or more medications daily, used by 46.4% of studies. Only 6.4% of articles distinguished between appropriate and inappropriate polypharmacy. Numerical definitions do not account for specific comorbidities and make it difficult to assess therapy safety and appropriateness in clinical settings. The review highlights the need for a more comprehensive and context-specific definition of polypharmacy to improve clinical decision-making and patient outcomes. The results suggest a shift towards using the term 'appropriate polypharmacy' to differentiate between prescribing 'many' and 'too many' drugs. The study emphasizes the importance of considering comorbidities and medication interactions when assessing polypharmacy. The review also notes the limitations of current tools and criteria used to identify inappropriate polypharmacy. Overall, the findings indicate a need for a more nuanced and evidence-based approach to defining and managing polypharmacy in clinical practice.