Of late, the ability of lanthanide-doped nanoparticles to upconvert NIR radiation into shorter visible and UV wavelengths has stimulated their use in biomedical diagnostics and bioimaging. As compared to the conventionally employed organic dyes and quantum dots for luminescence-based applications, lanthanide-doped upconversion nanoparticles offer several advantages such as the absence of background fluorescence improves the signal-to-noise ratio, a sharp emission bandwidth that facilitates multiplexed sensing platforms, high photostability, etc. More importantly, the tuning of emission to the biologically transparent window makes them an ideal candidate for deep tissues. However, the low quantum efficiency of these particles poses a major challenge in their practical applications. To improve the inherent quantum efficiency, the core–shell architecture is a method that is currently being exploited. The present chapter focuses on the various strategies available to tune the upconversion phenomenon in the core–shell architecture of upconversion nanoparticles and their application with an emphasis on the field of biomedical sciences. The chapter illustrates the concept of upconversion luminescence and the role of core–shell architecture on the emission behavior of upconversion particles. Additionally, various strategies are being adopted to tailor the upconversion luminescence by employing core–shell architecture such as core-inert shell and core-active shell are discussed in detail. Further, the role of lanthanide-ionic interactions, tailoring of emission lifetime and color, integration of multifunctionality, etc., to improve the quantum efficiency of UCNPs are accounted for here. In addition, an account of progress made in the synthesis of UCNPs-based core–shell particles and the applications in biomedical sciences including multimodal bioimaging, drug delivery, PDT, and so on are given. Finally, the conclusion part that illustrates the overall current status, challenges, and future perspectives of UCNPs-based core–shell architecture is also provided.