The concept that the physiological action of a substance is related to the chemical constitution of that substance has a history going back over a century to Alexander Crum Brown and Thomas R. Fraser. The founding of QSAR (Quantitative Structure–Activity Relationships) is more recent, but still goes back over half a century to the pioneering work of Corwin Hansch and Toshio Fujita, in addition to work from Albert Leo. QSARs have had a varied history in the field with many successes, but also the identification of limitations and approaches to combat these limitations. A summary of the history of QSARs is given along with background on where they have been applied and what improvements scientists have made in their application. This chapter will also cover elements of QSARs that relate more to the physicochemical properties under measurement, not just the biological activity or lack thereof.