PIWI proteins, a subclade of the Argonaute family proteins, are expressed predominantly in the germline and bind to PIWI-interacting RNAs (piRNAs), which are 25–31 nucleotides in length. The PIWI/piRNA pathway plays critical roles in germline development by regulating transposons and other targets to maintain genome integrity. While the functions of PIWI in the germline have been extensively investigated, recent studies have accumulated evidence that the human PIWI proteins, HIWI and HILI, are aberrantly expressed in a variety of cancers. This review summarizes our knowledge of PIWI expression in cancer and discusses its possible role in tumorigenesis.