Calcium Fluoride (CaF2) based luminescent nanoparticles exhibit unique, outstanding luminescent properties, and represent promising candidates as nanoplatforms for theranostic applications. There is an urgent need to facilitate their further development and applications in diagnostics and therapeutics as a novel class of nanotools. Here, in this critical review, we outlined the recent significant progresses made in CaF2-related nanoparticles: Firstly, their physical chemical properties, synthesis chemistry, and nanostructure fabrication are summarized. Secondly, their applications in deep tissue bio-detection, drug delivery, imaging, cell labeling, and therapy are reviewed. The exploration of CaF2-based luminescent nanoparticles as multifunctional nanoscale carriers for imaging-guided therapy is also presented. Finally, we discuss the challenges and opportunities in the development of such CaF2-based platform for future development in regard to its theranostic applications.