Less than a decade has passed since HDAC6 was first identified and regarded as an unusual histone deacetylase harbouring two catalytic domains. Early demonstration of its cytoplasmic localisation, its ubiquitin-binding and its tubulin-deacetylase activities took HDAC6 far away from everything known to involve other histone-deacetylases. Recent discoveries confirmed the very unique functions of HDAC6 among deacetylases and pointed to this protein as a master regulator of cell response to cytotoxic assaults. HDAC6 appears both as a sensor of stressful stimuli and as an effector, which, thanks to its wide range of activities, mediates and coordinates appropriate cell responses.