In routine practice, suspected metastases in patients with cancer are only occasionally biopsied, primarily because of the cost and invasiveness of the procedure. However, biopsies of metastatic lesions can be valuable, not only in confirming the presence of metastatic disease, but also in revealing unsuspected benign disease or secondary malignancies. In addition, such biopsies also allow the assessment of biomarkers that might differ from those on primary tumor cells, and can thereby facilitate selection of the optimal treatment. Because of the increasing recognition of clonal and phenotypic heterogeneity of tumors, we anticipate that in the near future, biopsying of metastatic lesions will constitute a standard-of-care practice, allowing assessment of molecular differences between the primary tumor and metastatic lesions. In our opinion, fine-needle aspiration is currently the best method for making repeated biopsies to monitor the tumor: it is minimally invasive, safe, and cost effective and can be coupled with modern ancillary techniques. Here we provide an up-to-date review of the clinical implications of tumor heterogeneity in metastatic disease and the ancillary molecular techniques used in cytology; we also discuss the role of modern cytology in contemporary diagnosis and management of metastatic cancer. Cancer (Cancer Cytopathol) 2014. © 2014 American Cancer Society.