AbstractAcylhydrazone‐based (macro)molecules display an increasingly broad spectrum of applications, from small therapeutic molecules and metal‐ions probes to self‐healing films and biorelevant dynamic polymers. The acylhydrazone function is indeed of prime interest since its unique design combines hydrogen bonds, pH‐dependent reversibility, ability to undergo molecular exchanges, and a possible polyvalency. However, a key parameter of its use in aqueous media is the associated water‐solubility of the resulting (macro)molecule. This property can indeed become a limitation for applications requiring high concentrations or no organic cosolvent. This review first focuses on describing the acylhydrazone function, its properties, and its relevancy in dynamic combinatorial chemistry. Then it details the synthesis strategies (molecular design, cosolvent, reaction conditions) reported in the literature to ensure a sufficient solubilization of both single‐bond and multiple‐bond acylhydrazone (macro)molecules, together with their various applications.