Hollow mesoporous silica nanoparticles (HMSNs), with a large cavity inside each original mesoporous silica nanoparticle, have recently gained increasing interest owing to their tremendous potential for cancer imaging and therapy. The last several years have witnessed a rapid development in the engineering of functionalized HMSNs (i.e., f-HMSNs), with various types of inorganic functional nanocrystals integrated into the system for imaging and therapeutic applications. In this article, we summarize the recent progress in the design and biological applications of f-HMSNs, with a special emphasis on molecular imaging. Commonly used synthetic strategies for the generation of high quality HMSNs will be discussed in detail, followed by a systematic review of engineered f-HMSNs for optical, PET, MRI and ultrasound imaging in preclinical studies. Finally, we discuss the challenges and future research directions regarding the use of f-HMSNs for cancer imaging and therapy.