In the first part of the talk we will discuss how we are laying the foundations for the design and architecture of the next-generation of distributed cyberinfrastructure. In the second part of the talk, we will introduce RADICAL-Cybertools -- a standards-based, abstraction-driven approach to High-Performance Distributed Computing. RADICAL Cybertools builds upon important theoretical advances, production software development best practices and carefully analyzed usage and programming models. We will discuss several science and engineering applications that are currently using RADICAL Cybertools to utilize DCIs in a scalable and extensible fashion. We will conclude with a discussion of the connection between the two challenges and thus the first steps towards the "Science of Cyberinfrastructure".