Establishing the diagnosis of mediastinal tumors is viewed as challenging. Why? One reason is that these are relatively rare conditions, meaning that very few physicians have a large experience. This is compounded by the fact that the number of different tumors and conditions is large, thus further segmenting mediastinal tumors into multiple even smaller subgroups. Furthermore, the fundamental nature of mediastinal lesions is quite varied, ranging from fulminant to indolent malignant tumors and from benign conditions with little impact on a patient’s life to life-threatening benign lesions. In addition, the features of a mediastinal lesion that are most useful to suggesting or establishing a diagnosis vary, including clinical presentation, imaging haracteristics, and microscopic appearance. There is a strong need from a management perspective to establish the diagnosis with a reasonable degree of confidence before a treatment intervention, yet the optimal approach to obtaining tissue is varied and depends on the suspected diagnosis. Finally, most clinicians lack a structure of how to approach mediastinal tumors, and often explore various avenues (i.e., imaging, biopsy) without a clear understanding of what is at the top of their differential diagnosis list and their rationale for a particular approach (e.g., liquid vs. tissue biopsy).