Systems Biology is aimed at analyzing the behavior and interrelationships of biological systems and is characterized by combining experimentation, theory, and computation. Multi-level models describe systems at different levels of organization and abstraction. To apply them in systems biology implies typically that concentration changes as well as the discrete behavior of single entities and their interactions need to be taken into account in modeling and simulation. A variety of approaches have been developed offering specific perspectives on cellular systems in modeling and simulation. We will explore how far multi-level aspects are already supported and identify challenges yet to be met.