Anti-apoptotic protein BCL-X plays a key role in tumorigenesis and cancer chemotherapy resistance, rendering it an attractive target for cancer treatment. However, BCL-X inhibitors such as ABT-263 cannot be safely used in the clinic because platelets solely depend on BCL-X to maintain their viability. To reduce the on-target platelet toxicity associated with the inhibition of BCL-X, we designed and synthesized PROTAC BCL-X degraders that recruit CRBN or VHL E3 ligase because both of these enzymes are poorly expressed in human platelets compared to various cancer cell lines. We confirmed that platelet-toxic BCL-X/2 dual inhibitor ABT-263 can be converted into platelet-sparing CRBN/VHL-based BCL-X specific degraders. A number of BCL-X degraders are more potent in killing cancer cells than their parent compound ABT-263. Specifically, XZ739, a CRBN-dependent BCL-X degrader, is 20-fold more potent than ABT-263 against MOLT-4 T-ALL cells and has >100-fold selectivity for MOLT-4 cells over human platelets. Our findings further demonstrated the utility of PROTAC technology to achieve tissue selectivity through recruiting differentially expressed E3 ligases.