Fusions of two different genes could lead to the production of chimeric RNAs, which could be translated into novel fusion (or chimeric) proteins. Fusion proteins often act as oncoproteins and drive cancer development, particularly in leukemia and lymphomas. Fusion proteins modify the existing protein-protein interaction (PPI) networks, which could eliminate some PPIs by removing protein domains in such fusions. This alternation of protein interaction networks could impact the signaling pathways and switch on the cancer-promoting activity that could drive the generation of cancer phenotypes and/or loss of controlled apoptosis. Thus, knowledge of the fusion proteins and their protein interaction networks could facilitate a deeper molecular understanding of cancer development, which could help to design new approaches for cancer therapies. Here, we discuss the structural features of fusion proteins and how they impact the PPI networks in cancers. Further, we discuss how to analyze the fusion protein-mediated alternation of PPI networks in cancers.