The overlap between large distributed simulations and real-time applications [1][2][3] has been always present, and it is increasing fast recently because of the circumstances raised from the current new trends, such as Cloud computing [4,5], intelligent transportation systems [1,6], green computing [7,8], and virtual environments [2,9]. As the overlap increases, new challenges appear, mostly for enabling applications, like serious gaming [10], virtual and augmented reality, and collaborative virtual environments [11], to execute seamlessly on distributed resources [12][13][14].This special issue intends to collect the state-of-the-art research works that include a set of concepts on high performance computing; design, modeling, and validation of distributed real-time systems; and multi-agent control and simulation systems. This issue also presents as objective to enable access to future trends and directions in the scope of simulations and real-time systems, covering cloud-based simulations, simulation in GPUs, and implementation of distributed virtual environment applications.Nine articles have been chosen from a strict selective process; all of these articles have been thoroughly reviewed by highly qualified anonymous referees. The articles cover a variety of important and challenging topics in the areas of large-scale distributed simulations and real-time systems.Matthew Forshaw, et. al.[15] present a new scalable simulator of High-Throughput Computing systems (HTC-Sim) incorporating real workloads and distinguishing itself by accepting to model multi-use clusters and interactive users. Their model is specially built to work with HTCSim and allow different HTC system policies to be incorporated in the simulation system. Being a large-scale simulation software, HTC-Sim provides the ability to model multi-use clusters and the presence of interactive users; thus, it enables fault tolerance and evaluation of server's energy consumption in HTC using different resource allocation policies.Arthur Valadares, Eugenia Gabrielova, and Cristina Lopes [16] introduce a conceptual framework for facilitating the design and testing of distributed real-time systems and applications. In their work, they define six properties and concerns while designing a Distributed Real Time (DRT) system. These properties are showcased in real-life, popular examples from different applicable domains in the field of distributed virtual environments. The re-evaluation of the concerns raised in this work shows the importance of some aspect in enhancing user quality of experience in such environments.Xiaosong Li, Wentong Cai, and Stephen John Turner [17] propose two major techniques in improving execution performance of Agent-based simulations on GPUs. Their innovative techniques consist of making use of an AgentPool and a location-based shared memory management. The AgentPool is introduced to support efficient agent creation and deletion and to enhance the CUDA native memory allocation for agent-based simulations. The memory management employs ...