Self-immolative polymers (SIPs) are unique macromolecules that are able to react to multiple types of environmental influences by giving amplified response outputs. When triggering moieties installed at SIP chain ends are activated by their corresponding stimuli, a spontaneous head-to-tail depolymerization ensues, often involving multitopic release of small molecules. SIP designs have evolved a high degree of modularity in each of their functional components, enabling a broad range of utility and applications-driven tuning. In this Perspective, we summarize and discuss recent progress in this nascent area of research, including (i) synthesis of different types of SIPs, (ii) design and evaluation of triggering moieties, (iii) depolymerization mechanisms and kinetics, (iv) applications of SIPs, and (v) outlook and challenges facing the field.