We found that ROR1 could serve as a receptor for Wnt5a, which could induce non-canonical Wnt-signaling that activates Rho GTPases and enhances leukemia-cell migration, proliferation, and survival. We find that high-level expression of ROR1 can accelerate development and progression of leukemia in transgenic mouse models and associates with more aggressive disease and shorter overall survival of patients with CLL. We have identified CLL cells express additional developmentally-restricted Wnt5a-receptors, namely ROR2 and RYK, which contribute to non-canonical Wnt signaling in CLL. We hypothesize that elucidation of the structure-function-relationships involved in signaling by ROR1 or other non-canonical Wnt will define clinically relevant biomarkers for non-canonical Wnt-signaling and identify novel targets for therapy. Moreover, inhibition of non-canonical Wnt-signaling could have therapeutic applications, alone or in combination with other newly developed targeted therapies that inhibit B-cell-receptor-signaling or BCL2.