Nuclear, casein kinase and cyclin-dependent kinase substrate (NUCKS), a protein similar to the HMG (high-mobility group) protein family, is one of the most modified proteins in the mammalian proteome. Although very little is known about the biological roles of NUCKS, emerging clinical evidence suggests that this protein can be a biomarker and therapeutic target in various human ailments, including several types of cancer. An inverse correlation between NUCKS protein levels and body mass index in humans has also been observed. Depletion of NUCKS in mice has been reported to lead to obesity and impaired glucose homoeostasis. Genome-wide genomic and proteomic approaches have revealed that NUCKS is a chromatin regulator that affects transcription. The time is now ripe for further understanding of the role of this novel biomarker of cancer and the metabolic syndrome, and how its sundry modifications can affect its function. Such studies could reveal how NUCKS could be a link between physiological cues and human ailments.