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In the last few decades, STAT5, (signal transducer and activator of transcription 5) has become an attractive therapeutic target but targeting of STAT5 has not been successful. In this dissertation, I report the development of AK-2292 as the first, potent and selective small-molecule PROTAC degrader of both STAT5A and STAT5B isoforms. Generally, having high affinity inhibitors is necessary in a successful PROTAC degrader development. However, due to the lack of reported STAT5 inhibitors with good binding affinities and selectivity for STAT5 over other STAT family proteins, I needed to develop our own STAT5 inhibitors. A class of STAT6 inhibitors reported by the McMurray group attracted my attention and served as a potential starting point based on our hypothesis that STAT6 inhibitors could bind STAT5 because the STAT5 and STAT6 sequence identity is 44 percent. Even though our initial trial compound was a very weak STAT5 ligand with a Ki value of over10 micromolar to STAT5 and with a Ki value to STAT6 of 5 micromolar, I was able to develop a class of small molecules that bind to STAT5 with low micromolar to sub-micromolar binding affinity and better affinity to STAT6. Exploiting the selectivity for STAT5 over STAT6 turned out to be challenging and unfortunately, the best STAT5 ligand showed no cell growth-inhibitory activity in representative chronic myeloid leukemia (CML) cell lines with activated STAT5. Fortunately, we were able to obtain the first co-crystals of our STAT5 inhibitors complexed with STAT5A, revealing the detailed structures and interactions between our inhibitors and STAT5A. This success has formed a solid basis for the development of a STAT5 PROTAC degrader. Employing the PROTAC technology, I successfully transformed these non-selective and non-effective STAT5 ligands into potent and selective STAT5 degraders exemplified by AK-2292, whose selectivity has been validated by various methods. AK-2292 exerts potent cell growth inhibition in a panel of CML cell lines and a subset of acute myeloid leukemia (AML) cells, both with activated STAT5. AK-2292 effectively induces STAT5 degradation in normal mouse tissues and human CML and AML xenograft tissues and achieves tumor regression in two CML xenograft models and one AML xenograft model in mice at well-tolerated dose-schedules. In chapter 1, the implications of STAT5 in hematologic cancers are discussed, followed by a description of current STAT5 inhibitor development and a brief description of proteolysis targeting chimera (PROTAC) technology. Chapter 2 describes the discovery of the first-in-class selective and efficacious STAT5 PROTAC degrader, AK-2292, and its extensive testing in vitro and in vivo, using CML cells. Chapter 3 focuses on our path to the discovery of STAT5 PROTAC degraders along with the detailed structure and activity relationship of both STAT5 inhibitors and STAT5 degraders, using AML cells. Finally, chapter 4 is a general discussion of the major achievements described in this dissertation and potential future research directions based on lessons learned during this dissertation research. This dissertation, taken as a whole provides intriguing insights into the first-ever selective targeting of the important transcription factor, STAT5. AK-2292, which was discovered in my research serves as an excellent compound with which to answer important biological questions raised in the study of STAT5 and importantly, it paves the way toward our ultimate goal of STAT5 targeted therapies for cancer and other diseases.