Polymers can be utilized to create formulations or delivery devices that allow a bioactive substance to exert a pharmacodynamic effect in a regulated manner. During the last two decades, polymers synthesized from natural sources such as polysaccharides and polypeptides have been utilized as a drug delivery system for various pulmonary disorders. Their key advantage is to create formulations or delivery devices that allow a pharmacologically active substance to enter the body in a regulated manner. Pulmonary pathologies are a widespread condition that affects people of all ages, sexes, and lifestyles worldwide, lowering the quality of life and shortening life expectancy. Several formulations/dosage forms are available for treating various pulmonary pathologies. Due to decreased bioavailability, adverse effects, and other toxic complications, novel natural polymer-based therapeutic and prophylactic pulmonary drug formulations are currently being used and rapidly investigated. Among natural polymer-based drug delivery systems, arginine, dextran, chitosan, sodium alginates, albumin, zein, and collagen are the most common natural polymers. All of these natural polymers have been used for a distinct application; for instance, to extend drug release, to ameliorate aerosol flow, to improve therapeutic effects, or for enhanced bioavailability and cellular uptake. While the list of known benefits of natural polymers continues to expand, there is still a significant gap in our understanding of their toxic mechanisms. This book chapter elucidates toxic effects and toxicodynamic mechanisms of natural polymer-based pulmonary drug delivery systems. Moreover, hemocompatibility of natural polymer-based drug delivery systems was also elucidated.