© 2019 Elsevier Inc. This review covers recent advances in the use of the squaramide moiety in chemical research. We focus on the varied applications of squaramides under the broad headings of self-assembly, organocatalysis, molecular recognition, medicinal chemistry, and bioconjugation and highlight several examples of each application. Squaramides are an intriguing class of compounds that, as a result of numerous advantageous properties, have found use across a diverse array of the chemical sciences. With their inherent ability to partake in strong bidirectional hydrogen bonding, in recent years, an explosion of research interest has led to a number of potential applications at the borders of materials science and biology, where new materials, molecular sensors, synthetic methodologies, and new drug candidates toward a diverse set of diseases have all been reported. With such a wide range of potential applications coupled with facile and robust synthetic approaches, it is clear that interest in the squaramide motif is likely to increase rapidly in the coming years. This review aims to summarize the recent uses of squaramides from scientific fields as diverse as supramolecular chemistry and chemical biology and to highlight the Brobdingnagian potential that this small building block has to effect real change and solve some of the challenges facing the world today.