For convenience to the patients and to increase compliance most drugs are given orally. Therefore high bioavailability is a key quest in most drug discovery projects. Low bioavailability usually results in undesired variability due to population differences. Early estimates of oral bioavailability can help to focus on most promising lead series and clinical candidates. This paper reviews some of the in silico attempts to predict oral bioavailability. However, bioavailability is a complex property and various pros and cons of current approaches will be discussed. Physiologically-based pharmacokinetic (PBPK) modelling is discussed as a promising approach to predict and simulate pharmacokinetics, including estimating bioavailability.