We present a general drug discovery strategy to find novel inhibitors of tyrosine kinases. This scheme includes the production of initial protein targets for primary screening, an evaluation of enzyme potency and specificity, biochemical and biological effects on various cellular processes in whole-cell models, and strategies for in vivo evaluation of antitumor activity. These aspects are illustrated using a newly discovered class of tyrosine kinase inhibitors, the 2-thioindoles. Certain members of this class of compounds inhibit specific tyrosine kinases at low micromolar concentrations and exhibit a distinct structure-activity relationship, as well as enzyme specificity depending on the chemical substitution. These compounds suppress growth factor-mediated tyrosine phosphorylation and mitogenesis in viable cells and, in some cases, exhibit marked specificity for these effects depending on the substituents on the indole ring system. The issue is stressed that since inhibitors of signal transduction pathways represent an entirely new class of potential antitumor agents, distinct from past and currently used cancer therapies, alternative in vivo tumor models may be needed as well as different requirements for dose levels, scheduling and endpoint evaluation. These inherent difficulties emphasize a need for more basic research at the in vivo stage of drug evaluation to enhance model development and provide a better understanding of the pharmacology for these newer classes of drugs.