Despite landmark achievements (e.g. >20 new anti-HIV drugs), a number of important therapeutic challenges remain. Although an expanding array of new drug discovery technologies has become available, drug research and development (R&D) productivity in general is still low. The establishment of close functional links between specialists active in early discovery, development and the clinic can thereby contribute to overall efficiency and higher success rates of new drug candidates. One of the more qualitative discovery challenges is to improve the predictability of early stage research models in term of in vivo drug efficacy. A cell-based model using viral replication in human T cells (MT-4) is used as an example from the HIV field to highlight the role of cell-based assays as tools for new target discovery, lead finding and optimization. The development of the next generation HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs) TMC125 and TMC278 and the protease inhibitor (PI) TMC114 (Prezista), further point to new fundamental strategies to combat and prevent antiviral drug resistance and to the importance of incorporating clinical and pharmaceutical aspects into lead finding and optimization, drug design and drug candidate selection. A more parallel-oriented drug discovery strategy is thus portrayed that harnesses some 'evolutionary' principles in combination with technologies that are currently rationalizing drug discovery.