Obesity is frequently complicated by a constellation of metabolic and cardiovascular anomalies, called the metabolic syndrome, which significantly increases morbidity and mortality of affected individuals. Insulin resistance is an important component of the metabolic syndrome. Protein tyrosine phosphatases (PTPs) that regulate insulin signaling are in principle excellent therapeutic targets for insulin resistance syndromes. The low molecular weight protein tyrosine phosphatase (LMPTP), encoded by the ACP1 gene, represents an attractive target in this family. LMPTP is highly expressed in adipocytes and there is strong in vitro and in vivo evidence that LMPTP is a negative regulator of insulin signaling and a promising drug target for obesity. Genetic association studies in humans support a role for LMPTP in insulin resistance and the metabolic complications of obesity. In vivo, partial knock-down of LMPTP expression by specific antisense oligonucleotides (ASOs) led to improved glycemic and lipid profiles and decreased insulin resistance in diet-induced obese C57BL/6 mice. This probe report describes the first (and first-in-class) selective allosteric LMPTP inhibitor, ML400 (CID 73050863, SID 173019983). ML400 is potent (EC50∼1μM), selective against other phosphatases, and displays good cell-based activity as well as rodent pharmacokinetics. As such it should be a valuable tool to explore the effects of selective LMPTP inhibition in vitro and in vivo.