<p>Chromosomal translocations are prevalent genetic events across multiple pediatric cancers, notably in CNS tumors, solid tumors, and leukemias. For decades, Fusion oncoproteins resulting from chromosomal translocations have been proposed as a hallmark of cancers, some of which can drive the process of cancers as the initial event of the disease. In addition, studies have shown that some tumor cells become addicted to the activity of fusion proteins, and cell death occurs when the fusion proteins are depleted. These researches suggest that fusion oncoproteins are one of the most promising targets for cancer treatment. Although fusion proteins are already recognized as critical oncogenic drivers, increasing evidence suggests that they can also form positive feedback loops with other proteins. In cancer patients, positive feedback loops have been shown to activate various oncogenic signals to drive tumor development, and influencing tumor cells’ sensitivity to different therapies. Therefore, these loops not only amplify the functions of the fusion proteins but also render single-agent targeting of the fusion protein insufficient to suppress tumor growth, highlighting the therapeutic potential of combination strategies in treating fusion-positive tumors. This review highlights the oncogenic roles of fusion protein-driven positive feedback loops in tumor initiation and progression, outline the molecular mechanisms underlying their formation and function, and summarize emerging therapeutic strategies targeting these circuits, offering new insights into the treatment of fusion-positive cancers.</p>