The chapter presents ten selected user interface and interaction challenges in extreme-scale visual analytics. The study of visual analytics is often referred to as “the science of analytical reasoning facilitated by interactive visual interfaces” in the literature. The discussion focuses on applying visual analytics technologies to extreme-scale scientific and non-scientific data ranging from petabyte to exabyte in sizes. The ten challenges are: in situ interactive analysis, user-driven data reduction, scalability and multi-level hierarchy, representation of evidence and uncertainty, heterogeneous data fusion, data summarization and triage for interactive query, analytics of temporally evolving features, the human bottleneck, design and engineering development, and the Renaissance of conventional wisdom. The discussion addresses concerns that arise from the different areas of hardware, software, computation, algorithms, and human factors. The chapter also evaluates the likelihood of success in meeting these challenges in the near future.