This year marks the 350th anniversary of the discovery of phosphorus by the alchemist Hennig Brand. However, this element was not included in the p-block of the periodic table until more recently. 2019 also marks the 150th anniversary of the preliminary tabular arrangement of the elements into the periodic system by Mendeleev. Of the 63 elements known in 1869, almost one-third of them belonged to what ultimately became the p-block, and Mendeleev predicted the existence of both gallium and germanium as well. The elements of the p-block have a disparate and varied history. Their chemical structure, reactivity, and properties vary widely. Nevertheless, in recent years, a better understanding of trends in p-block reactivity, particularly the behavior of those elements not typically found in biological systems, has led to a promising array of emerging applications, highlighted herein.