The clinical management of non-small cell lung cancer has shown unprecedented progress into the era of target therapies and immuno-oncology. Despite significant recent achievements in the treatment of these patients, identification of all the clinically actionable alterations required for patient management remains challenging, particularly when dealing with cytological or small bioptic samples. Many investigations have assessed the role of diagnostic tools currently available, including immunohistochemistry and sequencing assays. It is extremely important to be aware of the minimum adequacy criteria for pathology laboratories to ensure correct management of the biological samples in non-small cell lung cancer, including cytological, cell blocks, and histological specimens. In this review, the authors provide a comprehensive overview of the gold standard requirements, processing parameters, and turnaround time for the final integrated report, and additionally outline the values and limitations of the different bioptic strategies.