Publisher Summary This chapter aims to capture the sense of excitement and to describe the opportunities and challenges in the discovery and design of molecularly targeted small-molecule cancer drugs. Small-molecule targeted cancer drugs such as imatinib; erlotinib and others discussed in this chapter provide clear proof of concept that signifi cant clinical benefit can be obtained by developing drugs that act on the particular oncogenic abnormalities that are responsible for malignant transformation and progression. Drugging the cancer genome is now a reality. On the other hand, although the importance and utility of the molecularly targeted approach are now well established, cancer is still a formidably complicated disease and many challenges remain to be overcome. The most appropriate strategy for finding small-molecule leads is dependent on the nature of the molecular target and the associated biology. Molecular diagnostics are needed to select animal models and patients that are the most appropriate for assessing the activity of the particular agent. Molecular biomarkers are also absolutely essential to determine proof of concept for modulation of the desired target, and to help determine what is the optimal dose and administration schedule.