Pleural mesothelial cells have a primary cilium (PC), a solitary sensory organelle facing the extracellular environment. The BBSome is critical for the PC function and comprises several BBS proteins. Extracellular stimuli, like the ones encountered during a pleural effusion (osmotic, inflammatory, and oxidative stress-related signals) could influence the PC and BBSome. Using 2D and 3D culture models of benign mesothelial and primary malignant pleural mesothelioma cells we explored the BBSome components gene expression under hyperosmotic, inflammatory, and oxidative stress. We also assessed their effects in combination with PC perturbing drugs in the context of cell adhesion and cell migration, which are critical for tissue healing. These extracellular stimuli changed the expression patterns of BBS genes, while changes in cell adhesion were dependent on the cell and stimulus type. Cell migration was also sensitive to stress stimuli and the native PC length was critical in this context. Our results provide considerable insight into the molecular and phenotypical changes underlying PC responses of benign and malignant mesothelial cells to extracellular stimuli. Further research will be needed to assess the potential therapeutic implications of PC extracellular stimulation in malignant pleural disease.