Diabetes mellitus is a metabolic disorder characterized by elevated blood sugar levels resulting primarily from either a lack of insulin production or insulin resistance. Insulin elicits its effects by activating the Insulin Receptor (IR) which is responsible for glucose uptake and promotes insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of IR signaling and is responsible for dephosphorylating the tyrosine phosphorylated IR. Inhibition of PTP1B could thus promote glucose uptake [1]. Early PTP1B inhibitors, such as charged active site-directed analogs, showed poor cell membrane permeability. Subsequent uncharged mimetics overcome this initial hurdle however specificity over T-cell protein tyrosine phosphatase (TCPTP) was another challenge that needed to be overcome. Herein is an overview of the challenges faced for targeting PTP1B. These include the evaluation of compounds that target the active site, allosteric site, and finally covalent inhibition of this potentially viable drug target.