The DEAD box RNA helicases p68 (DDX5) and p72 (DDX17) play important roles in multiple cellular processes that are commonly dysregulated in cancers, including transcription, pre-mRNA processing/alternative splicing and miRNA processing. Although p68 and p72 appear to have some overlapping functions, they clearly also have distinct, nonredundant functions. Furthermore, their ability to interact with a variety of different factors and act as multifunctional proteins has the potential to impact on several different processes, and alterations in expression or function of p68 and/or p72 could have profound implications for cancer development. However, their roles are likely to be context-dependent and both proteins have been reported to have pro-proliferation or even oncogenic functions as well as antiproliferative or tumor cosuppressor roles. Therefore, eludicating the precise role of these proteins in cancer is likely to be complex and to depend on the cellular environment and interacting factors. In this article, we review the many functions that have been attributed to p68 and p72 and discuss their potential roles in cancer development.