Respiratory drug delivery systems present a promising approach for the treatment of various pulmonary diseases by directly targeting medications to the lungs. However, the development of effective respiratory drug delivery systems encounters several challenges, including overcoming the lungs’ innate defense mechanisms, achieving uniform drug distribution, and formulating stable and respirable drug particles. This chapter examines the anatomy and physiology of the respiratory system, focusing on aspects relevant to drug delivery, such as airflow dynamics, mucociliary clearance, and alveolar-capillary barrier function. Traditional methods of respiratory drug delivery, including metered-dose inhalers, dry powder inhalers, and nebulizers, are analyzed, elucidating their operational principles, advantages, and limitations. Recent advancements in particle engineering, device design, and formulation strategies are also investigated, with an emphasis on their potential to enhance the efficacy and precision of respiratory drug delivery. Novel approaches, such as nanocarriers, smart inhalers, and targeted delivery systems, are explored as promising avenues for addressing the challenges associated with respiratory drug delivery. Furthermore, the review underscores the importance of understanding the lung microbiome and harnessing the respiratory immune system for targeted drug delivery and immunomodulation. The integration of advanced imaging technologies, molecular biology, and computational modeling is anticipated to provide new insights into lung structure and function, paving the way for the development of personalized and targeted respiratory therapies.