This article evaluated volumetric molecular ultrasound (US) imaging with multi-targeted microbubble (MB) contrast agents for detection of angiogenic imaging biomarkers in a preclinical cancer model. Imaging was performed using a modified US system (Ultrasonix Medical Corp) equipped with a 4-dimensional (4D) transducer. Image processing software separated the US signal originating from intravascular MBs that were bound to the overexpressed targets from the freely circulating and unattached contrast agent. Molecular US imaging using targeted MBs was compared to results obtained using non-specific control MBs in the same prostate-cancer bearing mouse. Molecular US signals were significantly higher when imaging the targeted MBs versus imaging of control contrast agent (p < 0.001). Specifically, it was found that molecular US imaging of the targeted MB contrast agent produced a considerable mean intratumoral enhancement of 19.5 ± 2.2 dB. A significant inverse correlation was found between the molecular US signal and fractional tumor enhancement (ρ = -0.56, p = 0.02). This suggests that as the spatial distribution of the molecular US signal increases, the average intensity of the intratumoral reporter signal decreases. This finding could identify when the neovascularity is inadequate to meet the metabolic demands of the tumor, creating a strong angiogenic response. This high angiogenic response is typically found in aggressive cancers and during early stages of tumor growth. Therefore, molecular US imaging may improve US for the early detection of cancer and help distinguish indolent from aggressive disease.