The exciting advancements that we are currently witnessing in terms of novel materials and synthesis approaches are leading to the development of colloidal nanoparticles (NPs) with increasingly greater tunable properties. We have now reached a point where it is possible to synthesize colloidal NPs with functionalities tailored to specific societal demands. The impact of this new wave of colloidal NPs has been especially important in the field of biomedicine. In that vein, luminescent NPs with improved brightness and near-infrared working capabilities have turned out to be optimal optical probes that are capable of fast and high-resolution in vivo imaging. However, luminescent NPs have thus far only reached a limited portion of their potential. Although we believe that the best is yet to come, the future might not be as bright as some of us think (and have hoped!). In particular, translation of NP-based fluorescence imaging from preclinical studies to clinics is not straightforward. In this Perspective, we provide a critical assessment and highlight promising research avenues based on the latest advances in the fields of luminescent NPs and imaging technologies. The disillusioned outlook we proffer herein might sound pessimistic at first, but we consider it necessary to avoid pursuing “pipe dreams” and redirect the efforts toward achievable—yet ambitious—goals.