Well-defined GdPO4 hierarchical hollow spheres have been synthesized via a novel template-directed synthesis approach with 3-aminophenol-formaldehyde resin spheres as template. The core-shell structured precursor was firstly prepared by a homogeneous precipitation and subsequent hydrothermal route. Finally, the GdPO4 hollow spheres were obtained after an annealing process in air. The phase structure, morphology, and formation process were also investigated in detail. Moreover, the as-synthesized GdPO4 hollow spheres show good biocompatibility and excellent drug loading and sustained drug release ability. Interestingly, the lanthanide activator ions doped GdPO4 hollow spheres exhibit multimodal imaging functionality for combined optical and magnetic resonance imaging (MRI). Due to the well-defined hollow structure, good biocompatibility, luminescence properties, positive magnetic signal-enhancement ability, and drug loading/release patterns, the as-obtained GdPO(4 )samples may be potentially applied in fields of bioimaging, drug delivery, and disease diagnosis. Furthermore, this novel synthetic strategy may pave a critical way for the preparation of other similar lanthanide orthophosphate functional materials with perfect hollow spherical structure, tunable particle sizes, and good physicochemical properties.