Computer simulation of the dynamics of bio-molecular systems by the molecular dynamics technique yields the possibility of describing structure-energy-function relationships of molecular processes in terms of interactions at the atomic level. This is one of the reasons why computation based on molecular models is playing an increasingly important role in biology, biological chemistry, and biophysics. Since only a very limited number of properties of bio-molecular systems is actually accessible to measurement by experimental means, computer simulation can complement experiment by providing not only averages, but also distributions and time series of any definable – observable or non-observable – quantity, for example conformational distributions or interactions between parts of molecular systems. Present day bio-molecular modelling is limited in its application by four main problems: 1) the force-field problem, 2) the search (sampling) problem, 3) the ensemble (sampling) problem, and 4) the experimental problem. These problems, or rather challenges, will be discussed and in particular the pitfalls of comparing simulated with measured data will be illustrated using different examples. Perspectives will be outlined for pushing forward the limitations of computational modelling of bio-molecular systems.