Primary treatment for many solid cancers includes surgical excision or radiation therapy, with or without the use of adjuvant therapy. This can include the addition of radiation and chemotherapy after primary surgical therapy, or the addition of chemotherapy and salvage surgery to primary radiation therapy. Both primary therapies, surgery and radiation, require precise anatomic localization of tumor. If tumor is not targeted adequately with initial treatment, disease recurrence may ensue, and if targeting is too broad, unnecessary morbidity may occur to nearby structures or remaining normal tissue. Fluorescence imaging using intraoperative contrast agents is a rapidly growing field for improving visualization in cancer surgery to facilitate resection in order to obtain negative margins. There are multiple strategies for tumor visualization based on antibodies against surface markers or ligands for receptors preferentially expressed in cancer. In this article, we review the incidence and clinical implications of positive surgical margins for some of the most common solid tumors. Within this context, we present the ongoing clinical and preclinical studies focused on the use of intraoperative contrast agents to improve surgical margins. This article is categorized under: Laboratory Methods and Technologies > Imaging.