Small (2–28 nm) NaREF4 (rare earth (RE)=Nd–Lu, Y) nanoparticles (NPs) were prepared by an oil/water two-phase approach. Meanwhile, hydrophilic NPs can be obtained through a successful phase-transition process by introducing the amphiphilic surfactant sodium dodecylsulfate (SDS) into the same reaction system. Hollow-structured NaREF4 (RE=Y, Yb, Lu) NPs can be fabricated in situ by electron-beam lithography on solid NPs. The MTT assay indicates that these hydrophilic NPs with hollow structures exhibit good biocompatibility. The as-prepared hollow-structured NPs can be used as anti-cancer drug carriers for drug storage/release investigations. Doxorubicin hydrochloride (DOX) was taken as model drug. The release of DOX from hollow α-NaLuF4:20 % Yb3+, 2 % Er3+ exhibits a pH-sensitive release patterns. Confocal microscopy observations indicate that the NPs can be taken up by HeLa cells and show obvious anti-cancer efficacy. Furthermore, α-NaLuF4:20 % Yb3+, 2 % Er3+ NPs show bright-red emission under IR excitation, making both the excitation and emission light fall within the “optical window” of biological tissues. The application of α-NaLuF4:20 % Yb3+, 2 % Er3+ in the luminescence imaging of cells was also investigated, which shows a bright-red emission without background noise.