Considering the foundations, tools, and emerging discoveries of collaborative e-Work, as discussed in Chapters 1 and 2, it is realized that optimization and control are focused primarily on the core elements of e-Systems; agents, protocols, and workflows. In this chapter, we will show that these elements compose a solid framework for optimization and control of collaboration in emerging distributed e-Work systems. In order to be able to efficiently pass the benefits on to more complex constructs such as autonomous agents systems, production units configuration, highly reactive control protocols, and so on, these elements must be optimized as well. In order to show the evidence of the latest developments in optimization and control involving agent, protocol, and workflow theories, this chapter reviews the state-of-the-art techniques for achieving optimal design and operational control, and collaboration engineering. This chapter covers the incentives to construct autonomous agent-based systems, the key e-Criteria emerging from the transformation from traditional centralized work systems to decentralized e-Work systems, and several real-life applications of agent-based systems. Basic agent-based optimization and control architectures are reviewed along with pioneering bioinspired mechanisms based on swarm intelligence and natural evolution, and their impact on the intelligence and autonomy of agents. Several techniques for protocol and workflow optimization are also discussed.