Mas-related G-protein coupled receptor X1 (MRGPRX1) is a human sensory neuron-specific receptor and has gained increasing interest as a therapeutic target for the treatment of pain. Positive allosteric modulators (PAMs) of MRGPRX1 represent a promising new class of agents to treat pain by preferentially activating the receptors at the central terminals of primary sensory neurons, minimizing itch side effects caused by the activation of these receptors on the peripheral nerves. Our collaborative efforts supported by NIH's HEAL Initiative towards developing potent, orally available, thieno[2,3-d]pyrimidine-based MRGPRX1 PAMs will be presented.