The article discusses the challenges and advancements in multimodality imaging probes, particularly in clinical diagnostic imaging. It highlights the trade-offs between high sensitivity and resolution in different imaging modalities and the benefits of combining multiple modalities to enhance diagnostic capabilities. The first successful commercial fused instruments, such as PET/CT, have been widely adopted, followed by the development of PET/MRI systems, which offer improved patient safety and imaging capabilities. The surge in research on multimodal contrast agents has led to the development of probes that can detect multiple molecular targets simultaneously, enhancing the resolution and sensitivity of biological activity investigation. The article reviews various strategies for achieving multimodal functionality in a single probe, including lipid-based approaches, lipoprotein carriers, and nanoparticle designs. Lipid-based approaches involve encapsulating contrast agents into liposomes, either in the aqueous core or as part of the lipid membrane. Lipoproteins, such as LDL and HDL, have also been used to load multiple types of probes. Nanoparticle designs, particularly quantum dots, have proven versatile and effective for multimodal imaging due to their size and multicomponent nature. Methods for optimizing quantum dots for biological use, including conjugation, core/shell incorporation, and doping, are discussed. The article emphasizes the importance of ensuring that probes remain in the desired environment after liposome formation and the challenges of merging modalities with vastly different sensitivities. It also highlights the need for appropriate reporting standards, particularly for relaxivities, to facilitate the development and evaluation of multimodal imaging probes.The article discusses the challenges and advancements in multimodality imaging probes, particularly in clinical diagnostic imaging. It highlights the trade-offs between high sensitivity and resolution in different imaging modalities and the benefits of combining multiple modalities to enhance diagnostic capabilities. The first successful commercial fused instruments, such as PET/CT, have been widely adopted, followed by the development of PET/MRI systems, which offer improved patient safety and imaging capabilities. The surge in research on multimodal contrast agents has led to the development of probes that can detect multiple molecular targets simultaneously, enhancing the resolution and sensitivity of biological activity investigation. The article reviews various strategies for achieving multimodal functionality in a single probe, including lipid-based approaches, lipoprotein carriers, and nanoparticle designs. Lipid-based approaches involve encapsulating contrast agents into liposomes, either in the aqueous core or as part of the lipid membrane. Lipoproteins, such as LDL and HDL, have also been used to load multiple types of probes. Nanoparticle designs, particularly quantum dots, have proven versatile and effective for multimodal imaging due to their size and multicomponent nature. Methods for optimizing quantum dots for biological use, including conjugation, core/shell incorporation, and doping, are discussed. The article emphasizes the importance of ensuring that probes remain in the desired environment after liposome formation and the challenges of merging modalities with vastly different sensitivities. It also highlights the need for appropriate reporting standards, particularly for relaxivities, to facilitate the development and evaluation of multimodal imaging probes.