Provided herein are analogs of the natural product icariin represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. The analogs can be used to modulate (e.g., inhibit, such as by competitive inhibition) PDE5 and thereby treat a wide range of PDE5-mediated diseases, including cardiovascular, gastrointestinal, pulmonary, musculoskeletal, neurological and reproductive diseases. Also provided herein are compositions and methods including compounds of Structural Formula (I).