The Operetta CLS is a high throughput imager for High Content Analysis (HCA). It can acquire, analyze and manage confocal, brightfield and digital phase contrast images captured with a water immersion lens and can perform living cell imaging. Operetta CLS combines robust autofocusing, high power LED excitation with fast and precise mechanics to enable fast sequential acquisition. Our installation has a robotic plate handler so users can submit many samples for unattended analysis. Seamless integration with Harmony software provides an easy to use workflow, enabling the reliable discrimination of phenotypes even in complex cellular models. More than 30 ready-made analysis solutions (RMS) for the most common assays are included with Harmony software. Assembled from Harmony building blocks RMS can also be extended to new analysis solutions. Operetta CLS is a modular, highly configurable and field upgradable system that can be configured to meet the users applications.