Prognostic biomarkers have drawn significant attention in recent decades as a dependable, low-cost tool for not only early cancer diagnosis and screening but also for identifying other diseases such as CVD, diabetes, and parkinsonisms. Early identification improves the chances of successful cancer therapy and is regarded as the gold standard in cancer prevention. Gene mutations, gene expression, and promoter hypermethylation help stage aberrant cells before they become cancerous, making treatment more effective. Dysregulation of cyclin-dependent kinase inhibitors (CKIs) is linked to the genesis of the world’s most frequent malignancies. The identification and characterization of CKIs have increased our understanding of cell cycle checkpoints, considered the Holy Grail of cancer treatment. The G1/S checkpoint is frequently disrupted in malignancies, and CKIs play a crucial regulatory role at this checkpoint. So far, the INK4 family and the Cip/Kip family have been characterized as CKIs gene families. p16INK4A, p15INK4B, p18INK4C, and p19INK4D are members of the INK4 family, which bind to CDK4/CDK6 and limit their kinase activity by interfering with their connection with D-type cyclins. The CIP/KIP family, which includes p21CIP1, p27KIP1, and p57KIP2, binds to both cyclin and CDK subunits and modulates the activity of cyclin/CDK complexes, and has a wide range of inhibitory effects. The aberration of the INK4 and CIP/KIP families of CKIs contributed to the global progression of many leading cancers. However, p16INK4A and p27KIP1 show unique mutations, gene expression, and promoter methylation, implying that p16INK4A and p27KIP1 could be used as selective prognostic biomarkers for the screening and prevention of the world’s most leading cancers.