Inspired by the interesting contributions to the 6th Conference on Compu- tional Methods in Systems Biology (CMSB 2008) and the Dagstuhl Seminar 09091on"FormalMethods inMolecular Biology"inFebruary2009,papershave been selected for this special issue of the journal TransactionsonComputational Systems Biology, under the title Modeling Methodologies. The special issue starts with a position paper on "Biomodel Engineering - from Structure to Behavior", which discusses the potential that concepts from traditional computing science hold for creating more powerful models of biol- ical systems and identi?es venues for challenging future research. The technical contributions of the special issue covera broadrangeof mod- ing methodologies that have recently been developed in computational systems biology. First,twonewmodelinglanguagesarepresented.The"Attributed?-Calculus withPriorities"presentsacombinationofaconcurrentprocesslanguage,i.e.,the ?-calculus, and a sequential core language, i.e., the ?-calculus; being equipped withprioritiesthelanguageenablesthedescriptionofdiversespatialphenomena, di?erent kinetics, as well as an individual-based and population-based modeling of biological systems. It is shown how the di?erent dialects of the ? calculus, including the pi@-calculus, can be expressed. Its stochastic semantic is ?rmly rooted in CMTC's and is re?ected in the stochastic simulator.