In the complex landscape of cancer biology, the discovery of microproteins has triggered a paradigm shift, thereby, challenging the conventional conceptions of gene regulation. Though overlooked for years, these entities encoded by the small open reading frames (100-150 codons), have a significant impact on various cellular processes. As the pioneers of precision medicine delve deeper into genome and proteome, the spotlight now illuminates these small but mighty proteins, which is characterized by a single protein domain without any functional motifs. Till date, though only a small subset of them has been characterized, it has been demonstrated that these microproteins play a key role in fundamental biological processes such as RNA processing, DNA repair, and metabolism regulation. Techniques for identification and characterization such as ribosome profiling and proteogenomic approaches have unraveled unique mechanisms by which these microproteins regulate cell signaling or pathological processes against most of the diseases including cancer. However, the functional relevance of these microproteins in cancer remains a mystique. In this context, the current review aims to “rethink the essence genes” and explore “how the hidden players-microproteins orchestrate the hallmarks and signaling cascades of cancer, both as accelerators and brakes”.