Breast conserving surgery (BCS) is an effective treatment for early-stage cancers as long as the margins of the resected tissue are free of disease according to consensus guidelines for patient management. However, 15% to 35% of patients undergo a second surgery since malignant cells are found close to or at the margins of the original resection specimen. This review highlights imaging approaches being investigated to reduce the rate of positive margins, and they are reviewed with the assumption that a new system would need high sensitivity near 95% and specificity near 85%. The problem appears to be twofold. The first is for complete, fast surface scanning for cellular, structural, and/or molecular features of cancer, in a lumpectomy volume, which is variable in size, but can be large, irregular, and amorphous. A second is for full, volumetric imaging of the specimen at high spatial resolution, to better guide internal radiologic decision-making about the spiculations and duct tracks, which may inform that surfaces are involved. These two demands are not easily solved by a single tool. Optical methods that scan large surfaces quickly are needed with cellular/molecular sensitivity to solve the first problem, but volumetric imaging with high spatial resolution for soft tissues is largely outside of the optical realm and requires x-ray, micro-CT, or magnetic resonance imaging if they can be achieved efficiently. In summary, it appears that a combination of systems into hybrid platforms may be the optimal solution for these two very different problems. This concept must be cost-effective, image specimens within minutes and be coupled to decision-making tools that help a surgeon without adding to the procedure. The potential for optical systems to be involved in this problem is emerging and clinical trials are underway in several of these technologies to see if they could reduce positive margin rates in BCS.