Although content-based image retrieval has been studied for decades, most commercial image search engines are still text-based. However, there is a growing demand for techniques to support content-based image search at Web scale. In this paper, we propose an ambitious goal to searching one billion Web images by content, and discuss the major challenges and opportunities. We also present several important applications that can be greatly benefited by techniques to enable Web-scale image search by content. These applications include image copyright infringement detection, street-side photo search, and searchbased image annotation. We believe that the insights presented in the paper are enlightening to researchers in this field, and any breakthrough we make in this space will lead to many impactful applications in the future.