With the advent of high throughput, structure-assisted, and virtual screening an argument could be made that every target is now druggable. However, with an estimated 600-1500 possible druggable genes related to disease, the bottleneck now is judicious target choice; coupled with this is the choice of discovery strategy (target- vs system-based). This course discusses the pharmacological techniques available to relate targets to therapeutic opportunity, apply new ideas to re-visit mined out or apparently intractable targets, validation beyond targets (pathway-validation) and strategies to improve the disappointing 50% efficacy failure rate for new drug candidates.