Lung cancer is the current leading cause of cancer-related deaths worldwide, and malignant pleural effusion, an indicator of the advanced stage of this disease, portends a poor prognosis. Thus, making an accurate diagnosis of malignant pleural effusion is of paramount importance. During the past decade, the prognosis of patients with advanced non–small cell lung cancer has improved substantially, especially in those treated with targeted therapy and immunotherapy. The use of pleural fluid cytology should not only provide diagnoses but also aid in the selection of targeted therapies, especially when obtaining a histologic specimen is too difficult. In this evidence-based review, we address the importance of pleural fluid cytology in non–small cell lung cancer patients, from making the diagnosis to making treatment-related decisions when only pleural fluid is available.