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Piper longum (family Piperaceae), commonly known as "long-pepper" or "Pippali" grows as a perennial shrub or as an herbaceous vine. It is native to the Indo-Malaya region and widely distributed in the tropical and subtropical world including the Indian subcontinent, Sri Lanka, Middle-East, and America. The fruits are mostly used as culinary spice and preservatives and are also a potent remedy in various traditional medicinal systems against bronchitis, cough, cold, snakebite, and scorpion-sting and are also used as a contraceptive. Various bioactive-phytochemicals including alkaloids, flavonoids, esters, and steroids were identified from the plant extracts and essential oils from the roots and fruits were reported as antimicrobial, antiparasitic, anthelminthic, mosquito-larvicidal, antiinflammatory, analgesic, antioxidant, anticancer, neuro-pharmacological, antihyperglycaemic, hepato-protective, antihyperlipidaemic, antiangiogenic, immunomodulatory, antiarthritic, antiulcer, antiasthmatic, cardioprotective, and anti-snake-venom agents. Many of its pharmacological properties were attributed to its antioxidative and antiinflammatory effects and its ability to modulate a number of signalling pathways and enzymes. This review comprehensively encompasses information on habit, distribution, ethnobotany, phytochemistry, and pharmacology of P. longum in relation to its medicinal importance and health benefits to validate the traditional claims supported by specific scientific experiments. In addition, it also discusses the safety and toxicity studies, application of green synthesis and nanotechnology as well as clinical trials performed with the plant also elucidating research gaps and future perspectives of its multifaceted uses., (© 2022 John Wiley & Sons Ltd.)