Altered sialylation of cell surface glycoproteins and glycolipids is closely related to the malignant phenotype of cancer cells, including the metastatic potential and invasiveness. Many cancer-related antigens in clinical use contain sialic acids at the terminal position of sugar chains in the molecules. To elucidate the molecular mechanism, we focused our investigation on sialidase, which catalyzes the removal of sialic acid residues from the glycoconjugates. Four types of human sialidases identified to date behave in different manners during carcinogenesis. One of the sialidases, found in the lysosomes, showed downregulation in cancers, promoting anchorage-independent growth, and metastatic ability, while another, found in the plasma membrane, showed marked upregulation, causing apoptosis suppression. It was found that estimation of the mRNA levels of sialidases by real-time PCR allowed discrimination of cancerous from noncancerous tissues and even determination of the pathological stage in some cancers. Immunohistochemistry of cancer tissues using the antibody against the plasma membrane sialidase was useful for clinical diagnosis. This paper briefly summarizes our findings of the altered sialidase expression in cancers and the possibility of their clinical application as cancer markers. Human sialidases are indeed related to malignancy and may be potential targets for cancer diagnosis and therapy.