The three pillars in inhalation toxicology with scope to idealize testing strategies. Significant mammalian/human cell advances have been made (panel with left content). The conditions and strategies mimicking exposure in vivo have caught attention. The physicochemical environments in upper, middle, and lower respiratory lining such as pH, non‐aqueous component of mucus such as mucin, bimolecular composition, and salt microenvironment influence particle sedimentation. Dissolution and aggregation compromise the availability of these particulate matters on the cell surface to assess cell‐bioorganic matter interactions. Further, the versatile matter entering the inhalation pathway makes substantial contact with the microbiota in upper and lower respiratory lining for an extended period. Considering the complex physicochemical properties of these matters can create adverse effects on the microbial community and it has not been realized within in vitro toxicology (panel with middle content). Further, the exposure strategy following ALI at deep lung and dynamicity are additional key factors that need attention (panel with right content).