Photoswitchable fluorophores that can be toggled with visible light are extremely useful for applications in super-resolution imaging. However, most small-molecule photoswitches suffer from poor aqueous solubility and limited biocompatibility and require UV-light activation. Here, we report a novel class of biocompatible, visible-light-responsive fluorophores based on hemipiperazine (HPI) scaffolds with annulated π-systems─indolo-hemipiperazines (IndHPIs) and pyrrolo-hemipiperazines (PyrHPIs). These compounds display large Stokes shifts (up to 135 nm), reversible photoisomerization with up to 620 nm wavelength of light, and, in particular examples, enhanced fluorescence quantum yields and switching thereof, augmented by internal H-bonding. Selected compounds demonstrated excellent thermal stability of their E-isomers, with half-lives of up to ∼13,000 h at 50 °C, and high fatigue resistance under repeated switching cycles. Notably, certain IndHPIs are efficiently internalized by living cells and exhibit a reversible modulation of fluorescence upon irradiation. Further mechanistic studies revealed that regeneration of the brighter isomer is mediated by glutathione (GSH) likely a nucleophile-assisted isomerization pathway, providing a possible insight into the cellular behavior of these switches. The exceptional photophysical properties of IndHPIs position them as promising candidates for photoswitchable compounds for application in biological sciences and components of next-generation optical materials.