Targeted delivery of chemotherapeutics through the respiratory system is a potential approach to improve drug accumulation in the lung tumor, while decreasing their negative side effects. However, elimination by the pulmonary clearance mechanisms, including the mucociliary transport system, and ingestion by the alveolar macrophages, rapid absorption into the blood, enzymatic degradation, and low control over the deposition rate and location remain the main complications for achieving an effective pulmonary drug delivery. Therefore, particle-based delivery systems have emerged to minimize pulmonary clearance mechanisms, enhance drug therapeutic efficacy, and control the release behavior. A successful implementation of a particle-based delivery system requires understanding the influential parameters in terms of drug carrier, inhalation technology, and health status of the patient's respiratory system. This review aims at investigating the parameters that significantly drive the clinical outcomes of various particle-based pulmonary delivery systems. This should aid clinicians in appropriate selection of a delivery system according to their clinical setting. It will also guide researchers in addressing the remaining challenges that need to be overcome to enhance the efficiency of current pulmonary delivery systems for aerosols.