In breast cancer, tyrosine kinase-type cell surface receptor HER2-targeted therapies do not achieve a sustained inhibition of oncogenic signaling. Therapy-resistant tumors compensate for HER2 inhibition through several mechanisms, including increased expression of other cell-surface receptors most notably HER3. HER3 remains currently undruggable despite extensive clinical efforts. Durable efficacy of HER2-based therapy regimens requires, therefore, effective inhibition of HER2 and HER3. Our recent work has unraveled a previously unappreciated role of HER2 and HER3 intracellular trafficking in promoting drug resistance in breast cancer. Sortilinrelated receptor (SorLA) is a sorting receptor mainly investigated with regard to neuronal and metabolic diseases. We discovered oncogenic properties of SorLA through supporting HER2 and HER3 expression and signaling, thus mediating cancer response to growth factors to promote HER2-therapy resistance. Here we briefly review the mechanisms of SorLA supported oncogenic signaling in breast cancer and discuss their translational and clinical potential.