Advances in networking, high-end computers, large data stores, and middleware capabilities are ushering in a new era of largescale, distributed applications, which dynamically marshal resources across a heterogeneous, distributed environment. With these opportunities come new challenges. The overarching goal of the international workshops on the Challenges of Large Applications in Distributed Environments (CLADE) is to encourage novel solutions to the complex issues that arise in large-scale applications of distributed computation and to promote the development of innovative applications that effectively use distributed resources and adapt to a wide range of heterogeneity and dynamics in space and time. This goal includes development, deployment, management, and evaluation of large-scale applications in science, engineering, medicine, business, economics, education, and other disciplines, on Grids and other distributed heterogeneous and dynamic computing environments.This special issue is based on the 2003 and 2004 CLADE workshops held in Seattle, WA, and Honolulu, HI, respectively. It includes extended versions of seven representative papers from the two workshops that capture core issues from both the applications and enabling technologies perspectives. The papers are briefly introduced below.Addressing the challenges of large-scale applications in distributed environments requires the integration of efforts across many disciplines, from algorithms and programming models, to Grid systems middleware, to adaptive applications, data managers, and problem-solving environments that orchestrate the work of many components. We hope that the papers in this special issue will provide insight into these challenges and some innovative solutions, and will inspire further research in this area.