Purpose of Review <p>Recent strategies to treat nonadvanced SM have focused on targeted therapies to inhibit mast cell activation and/or proliferation. Several investigational approaches are being explored to treat nonadvanced SM in this targeted manner.</p> Recent Findings <p>Investigational approaches to treat nonadvanced SM have included targeting <i>KIT</i> D816V mutant receptor, siglec-8, mTOR, interleukin-6, and Bruton tyrosine kinase. Many of these different approaches have demonstrated potential efficacy and therapeutic benefit for diminishing symptoms and mast cell burden.</p> Summary <p>Clinical trials involving investigational treatments targeting <i>KIT</i> D816V mutant receptor are ongoing and have demonstrated the ability to improve symptoms, decrease mast cell burden, and improve patient quality of life. Other investigational approaches targeting siglec-8 and mTOR have demonstrated the potential to reduce symptoms in small patient cohorts. Results from targeted therapy with interleukin-6 did not support this approach being further pursued. Finally, a clinical trial targeting Bruton tyrosine kinase is also ongoing with no published data regarding efficacy or safety yet available.</p>