Gianni Pacella, Giuseppe Portale
Spiropyrans are a central class of molecular photoswitches whose reversible light‐induced isomerization between a closed, colourless spiro form and an open, coloured merocyanine form allows for their broad applicability in sensing, smart materials, and molecular machines. This review provides a structured framework for understanding how targeted chemical modifications can be used to control and fine‐tune the photochromic behaviour of these smart molecules. We first trace the historical evolution of spiropyrans, highlighting the development of nitrospiropyran as the prototypical photochrome and the branching of related families such as spirothiopyrans, spirooxazines, photoacids, and styryl cyanines. Particular emphasis is placed on how substituents, molecular strain, and heteroatom incorporation influence key properties such as absorption, thermodynamic stability, and switching efficiency. In addition to structural variations, we discuss how the use of acids to modulate photoisomerization led to the emergence of metastable‐state photoacids, providing unprecedented and reversible control over pH in aqueous environments. By systematically mapping structure–property relationships, this review highlights the delicate interplay between chemical design and environmental responsiveness in spiropyran systems. Overall, this review aims to serve as a comprehensive and practical guide for researchers seeking to design and apply spiropyran‐based photoswitches, thereby expanding their potential in photonic, chemical, and biological applications.