Sixty years have passed since Clark proposed the concept of glucose enzyme electrodes. Herein, we review major advances in such analyses based on electrochemical sensor systems over the past three decades that have paved the way to the leading role of wearable electrochemical sensing systems for non-invasive real-time chemical monitoring. These past developments of chemically modified electrodes, solid-contact potentiometric sensors, printable disposable electrodes, paper-based sensing devices, soft microfluidic detection systems, and miniaturized instrumentation along with the digital revolution and related advances in flexible electronics and material science have facilitated the evolution of wearable electrochemical sensors which have led to exciting possibilities for on-body analyses. Particularly, the introduction of non-invasive epidermal sensing platforms for monitoring health and wellness has been found fascinating and promising. Such skin-interfaced electrochemical sensors have shown to be extremely useful for continuous non-invasive biochemical monitoring of sweat and the interstitial fluid (ISF). A major driving force for these advances has been the large diabetes management market that has led to the introduction of self-testing glucose strips in the 1980s and continuous wearable glucose sensors in the 2000s. The current status of epidermal electrochemical sensors is discussed along with future prospects towards the broader scope and further integration and miniaturization towards the realization of complete lab-on-the-skin capable of multiplexed sensing of key biomarkers. Such use of wearable electrochemical sensors is expected to bring new opportunities in medical diagnostics, wellness, and nutrition, which will support the rapid changes from traditional, blood-centered diagnostics to decentralized personalized remote diagnostics.