The Knowledge Discovery Toolbox (KDT) enables domain experts to perform complex analyses of huge datasets on supercomputers using a high-level language without grappling with the difficulties of writing parallel code, calling parallel libraries, or becoming a graph expert. KDT provides a flexible Python interface to a small set of high-level graph operations; composing a few of these operations is often sufficient for a specific analysis. Scalability and performance are delivered by linking to a state-of-the-art back-end compute engine that scales from laptops to large HPC clusters. KDT delivers very competitive performance from a general-purpose, reusable library for graphs on the order of 10 billion edges and greater. We demonstrate speedup of 1 and 2 orders of magnitude over PBGL and Pegasus, respectively, on some tasks. Examples from simple use cases and key graph-analytic benchmarks illustrate the productivity and performance realized by KDT users. Semantic graph abstractions provide both flexibility and high performance for real-world use cases. Graph-algorithm researchers benefit from the ability to develop algorithms quickly using KDT's graph and underlying matrix abstractions for distributed memory. KDT is available as open-source code to foster experimentation.