Lanthanide-doped inorganic nanocrystals, possessing superior luminescence performance and photochemical stability, have attracted considerable attention due to their promising biological applications such as in bioimaging, biodetection, biotherapeutics and temperature sensing. Great progress has been made in achieving distinct and tailored optical properties for these functional nanocrystals in the past few decades. In this feature article, we summarize our recent advances in the realization of desirable and tunable luminescence for lanthanide-doped inorganic nanocrystals through local structure engineering that includes two main strategies, namely, externally morphological architecture design and intrinsically crystal structure regulation. As for the externally morphological architecture design, distinct optical performance achieved in lanthanide-doped nanocrystals with varied morphologies like core-shell, hollow and ultrasmall nanoarchitectures is summarized. With regard to the intrinsically crystal structure regulation, the tunable upconversion luminescence intensity and red-to-green ratio of Er for Yb/Er-doped nanocrystals and the consequent biodegradable nanocrystals are discussed, with an emphasis on the origin underlying the crystal-structure-dependent upconversion luminescence. Multifarious biological applications, including heterogeneous biodetection based on core-shell nanocrystals, homogeneous biodetection based on ultrasmall nanocrystals, superior nanothermometer based on hollow nanocrystals and in vivo bioimaging based on biodegradable nanocrystals, are briefly reviewed. Current challenges and future opportunities for lanthanide-doped inorganic nanocrystals for biological applications are also provided in the end.