text: Development and optimization of heavy metal lead biosensors in biomedical and environmental applications The detrimental impact of the heavy metal lead Pb on human health has been studied for years The fact that Pb impairs human body has been established from countless painful and sad historical events Nowadays World Health Organization and many developmental countries have established regulations concerning the use of Pb Measuring the blood lead level BLL is so far the only way to officially evaluate the degree of Pb exposure but the so called safety value 10 μg dL in adults and 5 μg dL in children seems unreliable to represent the security checkpoint for children through daily intake of drinking water or physical contact with a lower contaminated level of Pb contents In general unsolved mysteries about the Pb toxicological mechanisms still remain In this review article we report on the methods to prevent Pb poison for further Pb toxicological research We establish high sensitivity Pb monitoring and also report on the use of fluorescent biosensors such as genetically encoded fluorescence resonance energy transfer based biosensors built for various large demands such as the detection of severe acute respiratory syndrome coronavirus 2 We also contribute to the development and optimization of the FRET based Pb biosensors Our well performed version of Met lead 1 44 M1 has achieved a limit of detection of 10 nM 2 ppb 0 2 μg dL and almost 5 fold in dynamic range DR supported for the real practical applications that is the in cell Pb sensing device for blood and blood related samples and the Pb environmental detections in vitro The perspective of our powerful Pb biosensor incorporated with a highly sensitive bio chip of the portable device for quick Pb measurements will be addressed for further manipulation 