Polymers that depolymerize end-to-end upon cleavage of their backbones or end-caps, often referred to as “self-immolative” polymers (SIPs), have garnered significant interest in recent years. They can be distinguished from other degradable and stimuli-responsive polymers by their ability to provide amplified responses to stimuli, as a single bond cleavage event is translated into the release of many small molecules through a cascade of reactions. Here, the synthesis and properties of the major classes of SIPs including poly(benzyl carbamate)s, poly(benzyl carbonate)s, polyphthalaldehydes, polyglyoxylates, polyglyoxylamides, poly(olefin sulfone)s, and poly(benzyl ether)s are presented. In addition, their advantages and limitations as well as their recent applications in areas including sensors, drug delivery, micro- and nano-patterning, transient devices and composites, coatings, antibacterial, and recyclable plastics are described. Finally, the challenges associated with the development of new SIP backbones and their translation into commercial products are discussed.