As a very abundant neuropeptide in the brain and widely distributed peptide hormone in the periphery, neuropeptide Y (NPY) appears to be a multisignaling key peptide. Together with peptide YY, pancreatic polypeptide and the four human G protein-coupled receptor subtypes hY1R, hY2R, hY4R and hY5R it forms the NPY/hYR multiligand/multireceptor system, which is involved in essential physiological processes as well as in human diseases. In particular, NPY-induced hY1R signaling plays a central role in the regulation of food intake and stress response as well as in obesity, mood disorders and cancer. Thus, several hY1R-preferring NPY analogs have been developed as versatile tools to unravel the complex NPY/hY1R signaling in health and disease. Further, these peptides provide basic lead structures for the development of innovative drugs. Here, the current research is summarized focusing on the development of differently sized hY1R-preferring NPY analogs as well as their advances with respect to hY1R profiling, potential therapeutic applications and targeted cancer imaging and therapy. Finally, major limitations and innovative strategies for next generation hY1R-preferring NPY analogs are addressed.