With　the　rapid　development　of　nanotechnology,　the　unique　rare-earth　lanthanide-doped　upconversion　nanocrystals　(UCNs),　which　can　convert　tissue-penetrable　near-infrared　(NIR)　photonic　irradiation　into　ultraviolet,　visible,　and　NIR　emissions,　have　a　significant　potential　in　bioimaging,　diagnosis,　and　therapy,　as　well　as　in　photovoltaic　systems　and　optical　data　storage.　Despite　the　promising　achievements　made　in　the　past　decade,　critical　challenges　associated　with　low　upconversion　efficiencies　and　the　overheating　effect　induced　by　NIR　laser-irradiation　still　remain　in　the　biomedical　fields.　In　high　demand　are　more　well-defined　material　design　and　unique　structural　modifications　that　are　capable　of　solving　these　technical　concerns　and　promoting　such　promising　NIR　light-mediated　upconversion　nanocrystals　for　their　further　application　in　the　medical　sciences.　Recent　advances　in　upconversion　nanomaterials　have　witnessed　a　tremendous　development　towards　enhancing　their　photon　conversion　efficiency,　which　provides　great　opportunities　in　expanding　the　potential　of　the　UCNs　in　bioimaging　diagnosis　and　anticancer　therapy.　Hence,　this　review　is　mainly　focused　on　summarizing　the　fundamental　principles　and　strategies　that　improve　upconversion　luminescence　and　the　approaches　to　reduce　the　local　thermal　effect　on　the　basis　of　a　rational　design　of　UCNs.　In　addition,　the　future　perspectives　in　the　development　of　UCNs　for　biomedical　applications　are　also　proposed.