To describe the true behavior of most real-world systems with sufficient accuracy, engineers have to overcome difficulties arising from their lack of knowledge about certain parts of a process or from the impossibility of characterizing it with absolute certainty. Depending on the application at hand, uncertainties in modeling and measurements can be represented in different ways. For example, bounded uncertainties can be described by intervals, affine forms or general polynomial enclosures such as Taylor models, whereas stochastic uncertainties can be characterized in the form of a distribution described, for example, by the mean value, the standard deviation and higher-order moments. The goal of this Special Volume on Modeling, Design, and Simulation of Systems with Uncertainties is to cover modern methods for dealing with the challenges presented by imprecise or unavailable information. All contributions tackle the topic from the point of view of control, state and parameter estimation, optimization and simulation. Thematically, this volume can be divided into two parts. In the first we present works highlighting the theoretic background and current research on algorithmic approaches in the field of uncertainty handling, together with their reliable software implementation. The second part is concerned with real-life application scenarios from various areas including but not limited to mechatronics, robotics, and biomedical engineering.