Contrast agents designed to visualize the molecular mechanisms underlying cancer pathogenesis and progression have deepened our understanding of disease complexity and accelerated the development of enhanced drug strategies targeted to specific biochemical pathways. For the next generation probes and imaging systems to be viable, they must exhibit enhanced sensitivity and robust quantitation of morphologic and contrast features, while offering the ability to resolve the disease-specific molecular signatures that may be critical to reconstitute a more comprehensive portrait of pathobiology. This feature article provides an overview on the design and advancements of emerging biomedical optical probes in general and evaluates the promise of rare earth nanoprobes, in particular, for molecular imaging and theranostics. Combined with new breakthroughs in nanoscale probe configurations, and improved dopant compositions, and multimodal infrared optical imaging, rare-earth nanoprobes can be used to address a wide variety of biomedical challenges, including deep tissue imaging, real-time drug delivery tracking and multispectral molecular profiling.