This tutorial review traces the development of endo-regioselective epoxide-opening reactions in water. Templated, water-promoted epoxide-opening cyclization reactions can offer rapid access to subunits of the ladder polyethers, a fascinating and complex family of natural products. This review may be of interest to those curious about the ladder polyethers and their hypothesized biogenesis, about organic reactions in water, and about the development and application of cascade reactions in organic synthesis.