We systematically reviewed the results of the studies on expression regulation, biological functions, and clinical prognostic significance of CASP8AP2 gene. At present, the studies showed that the expression of CASP8AP2 gene was regulated by Homeobox proteins and DNA methylation, and could be silenced by miRNA-210. This protein was involved in apoptosis mediated by FAS and TNFα, NF-κB activation mediated by TNFα, regulation of gene expression induced by glucocorticoid and mineralocorticoid receptor, comprising Cajal body and histone locus body, transcription of replication-dependent histone, 3' end processing of histone, regulation of S phase progression, in addition to functioning as coactivator of transcription factors c-Myb and p73 to activating many genes' expression. On the other hand, low expression of CASP8AP2 gene was associated with relapse in childhood ALL. The deletion of this gene was related to the poor prognosis of children with T-ALL and T lymphoblastic lymphoma. Furthermore, 3 SNPs in this gene were possibly correlated with genesis of diffuse large B cell lymphoma and childhood leukemia. In conclusions, CASP8AP2 was a multifunctional protein. It could function to regulate cell proliferation, apoptosis, and gene expression. In childhood hematological malignancies, CASP8AP2 was a promising molecular marker with prognostic significance. Some SNPs were possibly correlated with leukemo- and lymphomogenesis.