After forty years of using glyphosate (phosphonomethyl glycine) in agriculture, the popular chemical faces an uncertain future. This broad spectrum systemic herbicide, commonly known as Roundup, has been used to manage weeds in many agricultural practices including a large volume of transgenic crops. Left uncontrolled, some of these weeds can reduce crop yields drastically. An herbicide that controls weeds only and does not affect the crop seems a perfect farming innovation, but the extensive use of glyphosate is causing reason for concern. Once considered a modern miracle and one of the most important advancements in weed control of the twentieth century, glyphosate has been increasingly marginalized as unsafe to human health. The historical success of Roundup may be unraveling as the consequences of overuse have left herbicide residues in multiple environments. Increasingly, there is credible evidence that glyphosate and its metabolites could adversely affect healthy cell development in humans, promoting the need for more study. This report highlights the important historical development of Roundup and Glyphosate Resistant (GR) crops, its unique mechanism of action, and accelerating evidentiary support of toxicity in human and ecological regimes.