RHOA is one of the most extensively investigated members of the Rho GTPase family of proteins and has long been implicated in malignant transformation as well as tumor invasion and metastasis. Recently, revolutionized sequencing platforms have revealed frequent RHOA mutations in a wide variety of human cancers, including angio-immunoblastic T-cell lymphoma, adult T-cell leukemia/lymphoma, germinal center B-cell lymphoma, diffuse-type gastric cancer, and other solid tumors. With their discrete positional distributions and types of amino acid substitution depending on cancer type, different RHOA mutations seem to have unique functional and biological properties. However, their impact on the development of different types of tumors remains controversial. Here, we present an overview of the current understanding of RHOA mutations in human cancers and highlight the unanticipated complexity of their genetic and biological properties.