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Pulmonary acute and chronic diseases, such as chronic obstructive pulmonary disease, pulmonary fibrosis and pulmonary hypertension, are considered to be major health issues worldwide. Cellular therapies with Mesenchymal Stem Cells (MSCs) offer a new therapeutic approach for chronic and acute lung diseases related to their anti-inflammatory, immunomodulatory, regenerative, pro-angiogenic and anti-fibrotic properties. Such therapeutic effects can be attributed to MSC-secretome, made of free soluble proteins and extracellular vesicles (EVs). This review summarizes the recent findings related to the efficacy and safety of MSC-derived products in pre-clinical models of lung diseases, pointing out the biologically active substances contained into MSC-secretome and their mechanisms involved in tissue regeneration. A perspective view is then provided about the missing steps required for the secretome "pharmaceuticalization" into a high quality, safe and effective medicinal product, as well as the formulation strategies required for EV non-invasive route of administration, such as inhalation. Unlabelled Image • MSC-secretome is proposed as cell substitute in acute and chronic lung diseases. • MSC-secretome has immunomodulatory, pro-angiogenetic and anti-protease properties. • MSC-secretome is safe and effective in pre-clinical models of lung diseases. • MSC-secretome must be formulated into quality, safe and effective medicinal product. • MSC-secretome intravenous and/or inhalation pharmaceutical dosage forms are needed. [ABSTRACT FROM AUTHOR]