Ultrasmall silica nanoparticles, as one type of nanocarriers featured by excellent biocompatibility and efficient renal clearance, are of rapidly growing interest for biomedical applications, particularly in oncology. Undesirably, the intrinsic issues of low site-targeting capability, short circulation time, and limited functionalities of ultrasmall silica nanoparticles severely impede their widespread application in the biomedical domain. Recent researches on surface modification for improved physical properties, enhanced site-specific abilities and multimodality imaging have been continuously emerging, which provide the prerequisite for possible application in the integration of diagnosis and treatment. On this basis, this review summarizes the most widely used synthesis approaches for well-ordered ultrasmall silica nanoparticles with uniform diameter and tunable pore size, and simultaneously highlights the diverse surface functionalization for versatile purposes and biomedical applications, including site-targeted delivery of drugs, stimuli-responsive cargo release, real-time bioimaging as well as cancer theranostics. Finally, the challenges of ultrasmall silica nanoparticles in oncology are further discussed with the aim of promoting their future clinical application.