The JAK-STAT signaling pathway and its dysfunction or genetic variation has been implicated in a number of haematological malignancies and autoimmune disorders, but despite this apparent central role in disease progression, Jak inhibitors often have limited efficacy in certain diseases likely due to persistent signaling. Here we describe the design, synthesis, and screening of Jak2 directed PROTACs that utilise cereblon as the E3 ligase system against various JAK-STAT driven cell lines and patient-derived xenograft models as an alternative to inhibition. This led to design of a Jak2 selective PROTAC containing a new phenyl glutarimide ligand as the cereblon ligand that displayed enhanced selectivity over GSPT1/2 which is a common off-target hit for PROTACs containing IMiD based cereblon ligands. These PROTACs selectively degraded Jak2 (>85%) over other Jak proteins with a DC50 of <20 nM in vitro. These PROTACs were efficacious in a patient-derived xenograft model ex vivo harbouring a JAK2 genetic alteration and were >10-fold more efficacious than the parent inhibitor baricitinib. This Jak2 selective PROTAC therefore provides a useful tool to study the effects of Jak2 degradation on cell survival and proliferation in various JAK-STAT driven diseases and explore the potential of targeted protein degradation as an alternative strategy to inhibition.