Recreating realistic features of the pulmonary acinus within an experimental model system is among the great challenges of modern respiratory physiology. Intricate anatomical architecture, distinct physiological flow patterns and complex cellular functions all render limited experimental approaches, capturing only some aspects of acinar airway physiology. Microfluidic-based in vitro devices (μFIVDs) offer attractive advantages over conventional in vitro models, and thus miniaturized technologies are becoming more frequently implemented to recreate biomimetic models of the pulmonary tract. However, current μFIVDs still lack critical physiological aspects of the pulmonary acinus; models are often limited to single channels and operate under submerged conditions that are loosely reflecting the realistic acinar environment. Here, we present an anatomically-inspired and physiologically-relevant cell-based in vitro microfluidic platform that combines a multigeneration design of ductal airways and alveolar spaces and integrates confluent monolayers of alveolar epithelium, recreating either fluid-submerged or air-exposed environments. Our microfluidic platform provides robust tools to study numerous aspects of pulmonary physiology, including varying alveolar morphology during fetal development, the propagation of liquid plugs alog airways and cytotoxicity of airborne particles deposited on alveolar walls. Overall, we propose a versatile model that captures anatomical and physiological pulmonary functionalities while preserving homeostatic cellular microenvironments.