AbstractThe precisely spatial‐temporal delivery of heterogeneous payloads from a single system with the same pulse is in great demand in realizing versatile and synergistic functions. Very few molecular architectures can satisfy the strict requirements of dual‐release translated from single triggers, while the self‐immolative systems based on dynamic covalent bonds represent the “state‐of‐art” of ultimate solution strategy. Embedding heterogeneous payloads symmetrically onto the self‐immolative backbone with dynamic covalent bonds as the trigger, can respond to the quasi‐bio‐orthogonal hallmarks which are higher at the disease's microenvironment to simultaneously yield the heterogeneous payloads (drug A/drug B or drug/reporter). In this review, the modular design principles are concentrated to illustrate the rules in tailoring useful structures, then the rational applications are enumerated on the aspects of drug codelivery and visualized drug‐delivery. This review, hopefully, can give the general readers a comprehensive understanding of the self‐immolative systems based on dynamic covalent bonds for delivering heterogeneous payloads.