Inorganic nanophotonic materials (INPMs) are considered to be promising diagnosis and therapeutic agents for in vivo applications, such as bio-imaging, photoacoustic imaging and photothermal therapy. However, some concerns remain regarding these materials, such as undesirable long-term in vivo accumulation and associated toxicity. The inability to be degraded or cleared has decreased their likelihood to be used for potential clinical translations. To this end, new strategies have recently emerged to develop systematically clearable INPMs. Thus, this review provides an overview of these strategies used to expedite the clearance of INPMs, as well as the relevant design and functionalized modifications which are available to engineer the above materials. Along with their important applications in the fields of in vivo diagnoses and therapies, the challenges and outlook for in vivo clearable INPMs are also discussed. This attempt to explore in vivo clearable INPMs to inhibit their accumulation toxicity may represent the solution to a ubiquitous physiological issue, thus paving a new avenue for the development of novel optical nanomaterials for biophotonic applications.