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Jiaye He, Jan Huisken (330 N Orchard St. Madison, WI, 53715, USA)Selective Plane Illumination Microscopy (SPIM) has revolutionized how long term in toto imaging is performed in a variety of biological fields. However, the combination of aberration and scattering from both the detection and illumination arms limits the imaging coverage of lightsheet systems for in toto applications. The most common approach to improve the imaging coverage uses sample rotation or multiple detection and illumination arms to provide additional optical access. In these schemes, predefined angles are chosen without knowledge of the sample condition. Isotropy in sample’s labelling density and optical property is an inherent assumption in these approaches which is never true in real-world experiments. Moreover, the amount of data generated scales linearly with the number of views whilst the information gain does not. Therefore, fixed-angle multi-view imaging is wasteful both in sample exposure time and storage space. Here we demonstrate a multi-view imaging scheme where information distribution is determined on the fly and calculated per angle to determine the optimal subsequent imaging orientation for optimal information gain.