Spindle cells seen in fine-needle aspiration biopsy (FNAB) of the mediastinal lesions can be a component of a wide variety of benign and malignant conditions. Few of these conditions, however, are described in the FNA cytopathology literature. This review discusses the cytopathologic features, differential diagnoses, and potential pitfalls of a variety of lesions with a significant component of spindle cells encountered in mediastinal FNAB. The cytopathology files from four institutions were searched for cases of mediastinal FNAB containing a spindle-cell component that was a key or predominant cytologic feature of the diagnostic specimen. The cytomorphologic features of these cases were analyzed, and their differential features are discussed. Of 196 mediastinal FNABs, 22 (11%) were lesions with significant spindle-cell component: granulomatous inflammation (four); benign nerve sheath tumor (four); thymic cyst (two); spindle-cell thymoma (two); large-cell non-Hodgkin's lymphoma with sclerosis (two); nodular sclerosing Hodgkin's disease (two); liposarcoma (two); spindle-cell squamous carcinoma possibly arising in a teratoma (one); unspecified high-grade sarcoma (one); spindle-cell malignant melanoma (one); and nonspecific fibrous tissue (one). The cytologic features of each lesion were analyzed as an aid for accurate classification. These findings were correlated with radiologic and clinical information when available. The value of ancillary studies performed on aspirated material in selected cases was also reviewed. FNA of mediastinal lesions with significant spindle-cell morphology represents an infrequent and heterogeneous group of entities that may pose significant diagnostic challenges. This review presents the salient cytopathologic features of various spindle-cell lesions of the mediastinum with particular emphasis on differential diagnosis and pitfalls. The pathologist must use caution when interpreting these lesions and ancillary studies may be of significant value in selected cases.