Introduction: Thoracic neoplasms present a significant diagnostic challenge due to the anatomical complexity of the thorax and the morphological overlap between pulmonary, pleural, mediastinal, and metastatic tumors. Although imaging techniques allow for adequate localization of lesions, their ability to establish tumor type is limited. In this context, immunohistochemistry (IHC) has become a key tool for differential diagnosis, enabling precise characterization with diagnostic, prognostic, and therapeutic impact. The objective of this study is to describe the utility of IHC in a case series of complex thoracic neoplasms. Methodology: A retrospective case series was conducted, including five patients evaluated over the past three years at a tertiary care institution in the city of Cúcuta. All cases were discussed in a multidisciplinary thoracic team. Histological samples were obtained via percutaneous biopsies, thoracoscopy or surgical resection. Specific immunohistochemical panels were applied according to the diagnostic suspicion, including epithelial, mesothelial, mesenchymal and cell proliferation markers. Results: Immunohistochemistry allowed definitive diagnosis in all cases where imaging and conventional morphology proved insufficient. The Ki-67 index provided relevant prognostic information, identifying malignant behavior in mesenchymal tumors. Correct immunohistochemical classification was associated with favorable clinical outcomes in resectable cases. Conclusion: Immunohistochemistry is an essential and highly effective tool in the differential diagnosis of thoracic neoplasms. Its systematic integration into clinical practice allows for precise tumor classification, guides multidisciplinary management, and optimizes therapeutic decisions, establishing itself as a fundamental pillar of modern thoracic oncology.