The IGF1 receptor (IGF1R) plays important roles in tumor cell proliferation and survival and its inhibition may be therapeutic in several human cancers. OSI Pharmaceuticals has developed a series of potent imidazo[1,5-a]pyrazines that selectively inhibit IGF1R both in vitro and in vivo. The SAR developed within this series provides some insight into key factors for selectivity, potency, and optimized pharmacokinetics. Structure-based insights bolster these empirical observations. The properties of an advanced lead compound, PQIP, will be discussed in detail. This series of compounds affirms that a strategy targeting IGF1R with small molecule kinase inhibitors can yield novel development candidates to treat human cancer.