The Operetta is an automated epi-fluorescence microscope system for end point HCS-assays. The system is equipped with a xenon lamp (360-640nm continuous spectrum) and a LED light source for transmission mode, enabling multiple wavelength fluorescence and brightfield high-resolution imaging. The Microscope can be used with standard 96-well and 384-well microplates , but also provides a function to create user-defined plate formats. Our Operetta is equipped with 10X, 40X and 60X high NA and a 20X long WD objective. The instrument is integrated into a small robotic unit (Plate::HandlerTM-II and three hotels) which enables unattended image acquisition of multiple assay plates. Measurement set-up, image acquisition, data analysis and data base storage are all performed in Harmony High Content Imaging and Analysis Software.