A substantial proportion of childhood cancers are attributable to an underlying genetic syndrome or inherited susceptibility. Recognition of affected children allows for appropriate cancer risk assessment, genetic counseling, and testing. Identification of individuals who are at increased risk to develop cancers during childhood can guide cancer surveillance and clinical management, which may improve outcomes for both the patient and other at-risk relatives. The information provided through this article will focus on the current complexities involved in the evaluation and management of children with cancer-predisposing genetic conditions and highlight remaining questions for discussion.