Heuristic search is a fundamental technique for solving problems in artificial intelligence. However, many heuristic search algorithms, such as A* are limited by the amount of main memory available. External memory search overcomes the memory limitation of A* by taking advantage of cheap secondary storage, such as disk. Previous work in this area assumes that edge costs fall within a narrow range of integer values and relies on uniformed search order. The goal of this dissertation research is to develop novel techniques that enable heuristic search algorithms to solve problems with real values using a best-first search order while exploiting external memory and multiple processors. This work will be organized into four components. The first component will discuss external memory search and present a novel technique for incorporating real-valued edge costs. The second component will present a novel algorithm for solving problems with large branching factors with application to the challenging problem of Multiple Sequence Alignment (MSA). The third component will cover bounded suboptimal external search for practical MSA applications. The final component of this research will be the development of a novel distributed search framework; allowing parallel and external memory heuristic search algorithms to run cooperatively on a commodity computing cluster. Together these four components will enable heuristic search to scale to large problems in practical settings while exploiting modern hardware.