Diabetes has long been recognized as one of the leading causes of death in the United States and worldwide second only to cancer and heart-related ailments. Diabetes is a silent killer and early stage diagnosis and controlling blood glucose level is the key to maintain and control the disease. Blood glucose levels are typically monitored with the help of glucose detection through electrochemical oxidation of glucose to gluconic acid or gluconolactone. Typically, in conventional glucose detectors, enzyme-based electrochemical sensors are used which suffers from several critical challenges including reduced efficiency and sensitivity, reduced shelf lives, lack of long-term stability (due to enzyme denaturation), high fabrication cost (due to complex enzyme purification steps), and high detection limit (due to less efficient indirect electron transfer). In this presentation we will discuss about designing high-efficiency direct glucose electrochemical sensors from transition metal chalcogenides using principles of materials chemistry, specifically, tuning the redox potential of the transition metal site. We will present several examples of high-efficiency chalcogenide based glucose sensors including CoNi2Se4-rGO nanocomposite, Ni3Te2, Cu2Se, and NiSe. These chalcogenide based electrocatalysts show high activity for glucose oxidation at very low potential (~0.35 - 0.45 V vs Ag|AgCl) with high sensitivity (exceeding 18 mA/mM cm2) and low limit of detection (LOD). These chalcogenides can offer direct electron transfer pathways over a wide potential range leading to much higher sensor efficiency. Moreover, the sensing performance of these electrocatalysts were tested in presence of common interferents present in physiological samples such as dopamine, ascorbic acid, lactose, etc., where it showed that glucose sensing was unaffected primarily because at such low potential, other biomolecules are not affected. In fact, the ability to oxidize glucose at such low potential is considered to be one of the most prominent novelty of these chalcogenide electrocatalysts, and the glucose oxidation potential of 0.35V (CoNi2Se4) is one of the lowest reported potential till date. The reason for such high activity for glucose oxidation was investigated through a series of experiments designed to alter the redox potential of the transition metal site either by changing the anion (selenide to telluride), transition metal doping (NiSe vs CoNi2Se4), or changing the d-electron occupancy (NiSe vs Cu2Se). Through these measurements we observed that on changing the electronegativity of the anion from selenide to telluride, the glucose oxidation potential could be reduced further due to transition metal site oxidation occurring at a lower potential. The transition metal site oxidation can be considered as the catalyst activation step which initiates the glucose oxidation. Transition metal doping at the active site also helped to redistribute the electron density thereby influencing catalyst activation and subsequent glucose oxidation steps. Interestingly, using highly occupied d-orbitals, slowed the electrocatalytic process. In this presentation we will discuss in details these structure property correlation and other factors influencing the electrocatalytic activity. We will also discuss how nanostructuring of the electrocatalysts on the other hand, increases the catalytic efficiency manifold by increasing the functional surface area for catalytic activity. Electrochemical measurements as well catalyst synthesis and processing will be discussed in details in this presentation.