In the pure technological era we are living, the need for appropriate tools, methods, and approaches that could boost and skyrocket real world various applications is of paramount importance even for daily life. Toward this direction, in the up-to-date literature, several computational tools are offered, new advanced nearly real-time performing techniques are introduced, almost every day, and powerful computing approaches are promising to tackle the issues of performance, energy efficiency, and computational burden, with many different fruitful ways. Nevertheless, most of these demands, trends, and perspectives would have never met the expected outcome without the help of modern high performance computing systems able to model and simulate computationally intensive scientific applications in the most efficient and appropriate way. Consequently, numerous and various high performance computing approaches like multi-/manycore systems, accelerators, compute clusters, and massively parallel machines, when combined with efficient numerical methods for differential equation systems and native computational paradigms, enable scientists and researchers worldwide to significantly advance the application of computing methodologies in research and industry applications, both in qualitative but mainly in quantitative way.In this aspect, this Special Issue aimed to offer both scientists and engineers in academy and industry an opportunity to express and discuss their views on current trends, challenges, and state-of-the art solutions to various problems in High Performance Computing for Modeling and Simulation. More specifically, in this Special Issue, both theoretical aspects of high performance computing systems, like libraries for the reduction of the programming burden of numerical models on heterogeneous parallel architectures, hybrid programming model MPI/OpenMP for tackling the communication load imbalance issues, and applications starting with parallel shared-memory version of the Space Saving algorithm for mining items, approximate and semi-asynchronous parallel model for supporting Parallel and Discrete Event Simulation, parallel execution pipeline of an existing description algorithm capable of characterizing both color and texture information of a given feature point for robotic visual place recognition, and parallel and hardware acceleration of detection of ambiguous objects for surveillance reasons, as well as optimization techniques to be parallelized such as Imperialist Competitive Algorithm, are fully considered in a fruitful and plausible way.In more details, the article by Chakroun et al 1 described ExaShark, 2 an open source library with the aim of reducing the programming burden of numerical models on heterogeneous parallel architectures. The presented library offers a global-array-like interface, whereas its run-time can be configured to use shared memory threading techniques, inter-node distribution techniques, or combinations of both. ExaShark takes advantage of the latest HPC technologies, helping to ...