Nanomaterials have been ubiquitously employed as platforms to load imaging agents for cancer diagnosis. In general, the majority of nanomaterials are accumulated in the reticuloendothelial system (RES)-associated organs such as liver, spleen, and lung after systemic administration. Although the adopted strategy used to modify nanomaterials with polyethylene glycol (PEG) has relieved this problem to some extent, challenges still remain for further clinical applications. Recently, nanomaterials with zwitterionic surface modification have been found to have a better antifouling property than those with PEGylation modification. This Topical Review reports the recent progress in the development of zwitterion-modified nanomaterials for improved cancer cell diagnosis, including zwitterionic modification of hybrid nanoparticles for enhanced fluorescence, computed tomography (CT), magnetic resonance (MR), and dual-mode imaging of cancer cells, and the zwitterionic modification of nanofibers for specific capture of circulating tumor cells with improved capture purity and efficiency. Challenges and future perspectives in this particular field are also discussed.