Immunohistochemistry has come to occupy a key position among the armamentarium of tools pathologists apply to the evaluation of lung and pleural neoplasms. This technique uses antibodies that bind to specific antigens, usually proteins, enabling microscopic detection of the antigens. Over the last several decades, an impressive array of antibodies has become commercially available, and many of these antibodies have become integrated into the routine practice of pathology. Evaluation of tissue or cytology samples with these antibodies can facilitate determination of tumor type and site of origin. Comments citing results of immunohistochemical staining with these antibodies frequently appear in pathology reports and may be difficult to translate for those less familiar with the technique. This review presents, in two parts, common diagnostic applications of immunohistochemistry with information about strategies taken for frequently encountered differential diagnostic scenarios. This article is the second of the two parts and focuses on immunohistochemical approaches to differentiating primary pulmonary from metastatic adenocarcinomas, mesotheliomas from carcinomas, and various types of spindle cell neoplasms. Potential future directions involving therapeutic and prognostic biomarkers are also discussed.