Dual-energy mammography (DEM) is a recently FDA-approved x-ray imaging technology developed for breast cancer screening, especially advantageous for women with dense breasts. While studies have reported the benefits of DEM in breast cancer screening, thus far, no DEM-specific contrast agents have been approved. Therefore, clinics use iodinated contrast agents, which can have suboptimal contrast in DEM, short circulation half-life, and adverse effects on patients. Nanoparticle-based contrast agents can be designed to address some of these limitations. This thesis explores different materials to develop DEM-specific nanoparticle-based contrast agents with high contrast and biocompatibility. Based on previous research highlighting elements that produce high DEM contrast, we explored materials such as silver, tellurium, and molybdenum to develop DEM-specific nanoparticle-based contrast agents. First, 8 nm silver telluride nanoparticles (Ag2Te NPs) were developed as DEM-specific contrast agents. Ag2Te NPs are composed of two DEM high-contrast generating materials and thus, provide superior contrast than iodinated molecules, both in in vitro and in vivo settings. Additionally, by coating these with mPEG-SH 5K, we prolonged their circulation, tumor accumulation, and colloidal stability while maintaining biocompatibility. Next, to further improve the likelihood of clinical translation of Ag2Te NPs, we designed them to be 3 nm in size to achieve renal clearance. These 3 nm Ag2Te NPs provided similar contrast and biocompatibility to the larger Ag2Te NPs, even when studied for a longer term in vivo. Furthermore, 93% of the injected dose was excreted from the main organs in 24 hours, 95% in 7 days, and 97% in 28 days. This excretion is among the highest reported thus far for any nanoparticle type. Lastly, we developed 2 nm molybdenum disulfide nanoparticles (MoS2 NPs) with different coatings and explored them as DEM-specific contrast agents. Our findings suggest that MoS2 NPs can produce higher contrast than iodinated molecules and be biocompatible in vitro. Together, this work presents an advancement in the development of DEM-specific contrast agents and their potential progression towards clinical translation.