Primary malignancies of the lung represent a heterogeneous group of neoplasms with the highest mortality and frequency in men and women combined [1], with age-standardized incidence and mortality of, respectively, 22.4 and 18.0 per 100,000 people [2]. Even though its incidence in the Western world has been constantly declining since the mid-1980s of the last century, in 2022, about 237,000 new diagnoses and 130,000 deaths are estimated in the US (69,000 men, 31,000 women). Most of the lung cancers are classified as non-small cell lung cancer (NSCLC, 82%) and small cell lung cancer (SCLC, 14%) [3]. The main risk factors for the development of the disease are represented by cigarette smoking (80–90% of affected patients have a positive history of smoking), either active or secondhand, radon gas, aging, and environmental or occupational exposure to carcinogenic agents (at least 10% of total cases of lung cancers present a previous history of occupational exposure) [1,2,3,4]. Most patients come to clinical and diagnostic evaluation because of suspicious symptoms or incidental abnormal findings on chest imaging. Nowadays, several different techniques are available in order to determine a definitive diagnosis: selecting a specific diagnostic modality should maximize the diagnostic yield and avoid distressful and unnecessary tests for the patient. FDG-PET/CT combines both conventional and metabolic imaging [5]. This hybrid modality detects lesions with an avid glucose metabolism, a feature highly consistent with malignant lesions; however, some indolent lung cancers may demonstrate a weak metabolic activity, while a wide spectrum of flogistic non-neoplastiv conditions could show a high FDG captation. Sputum cytology is the least invasive diagnostic modality, and its main indications are for central lesions (mainly squamous cell cancers) and bloody sputum, but its accuracy is widely influenced by sputum collection. Flexible broncoscopy (FB) forcep biopsy shows a high diagnostic yield for central lesions, but its sensitivity for peripheral cancer is considerably lower; radial EBUS (R-EBUS) is an adjunct imaging modality for suspicious peripheral lung nodules, especially in patients for whom surgery is not indicated [6], and it brings real-time ultrasound images in order to better assess the ideal location of sampling. Among surgical techniques, small solid peripheral nodules are amenable for video-assisted thoracoscopy (VATS) [7] and, along with open biopsy, provide the largest pathology specimens. However, surgical methods are inevitably associated with higher rate of complications and longer post-operative recovery. Percutaneous image-guided biopsy of the lung (with ultrasound, tomographic, and/or fluoroscopic guidance) allows to carry out microhistological and cytological samples using minimally invasive procedures, resolves diagnostic suspicion, and early addresses the diagnostic-therapeutic path, resulting in a reduced discomfort for the patient and a significant decrease in frequency and entity of intra- and periprocedural complications, in comparison with surgical biopsy techniques [8,9]. In the era of personalized and precision medicine, constant improvements in molecolar tissue characterization and in pathologic assessment techniques broadly speaking (e.g., immunohistochemistry staining and direct gene sequencing), along with progression in imaging techniques, have led to a considerable growth of indications for percutaneous biopsy. Nowadays, these procedures are also performed to assess disease progression and prognosis and to eventually provide personalized therapy. The future will, therefore, rely more on biopsies, with the consequent need for more adequate cytologic and histologic samples [10,11,12]. The main limitation of transthoracic biopsy procedures is, however, represented by the high relative rate of some complications: among these, pneumothorax (PNX) is the most common, showing an incidence up to 60% and an average risk of about 20%, even though chest tube placement is required with a reported rate of only 1 to 14% [13,14,15]. Several risk factors are associated with pneumothorax, such as lesion size and depth, experience of radiologist, number of pleural punctures, non-perpendicular needle angle to pleura, and the imaging evidence of chronic obstructive pulmonary disease [14,16,17]. Pulmonary hemorrhage (PH) is the second most frequent complication: it can be identified as perilesional ground-glass opacity and shows occurrence rates from 4 to 27%, with hemoptysis risk up to 5%. Bleeding is proved to be more frequent when the lesion is 4 cm [14,18]. Other rare complications are systemic air embolism and tumor seeding (reported rates of 0.06% and 0.01–0.06%, respectively) [15]. The aim of this single-center, observational retrospective study is to evaluate the diagnostic accuracy of CT-guided core-needle biopsy (CNB) in the diagnosis of primary malignant neoplasms of the lung and to compare the results with the evidence from the most accredited state-of-the-art literature.