High-throughput screening technologies in biological sciences of large libraries of compounds obtained via combinatorial or parallel chemistry approaches, as well as the application of design rules for drug-likeness, have resulted in more hits to be evaluated with respect to their ADME or DMPK properties. The traditional in vivo methods using pre-clinical species such as rat, dog, monkey, are no longer sufficient to cope with this demand. This contribution discusses the changes towards medium to high-throughput in vitro and in silico ADME screening [1]. In addition much more attention is now put on early safety and risk assessment of promising lead series and potential clinical candidates.