Professor Steven Treon discusses the rationale for targeting the toll-like receptor/B cell receptor (TLR/BCR) pathway in indolent lymphomas like Waldenström’s macroglobulinemia (WM) and marginal zone lymphoma (MZL). He focuses on genomic variants and therapeutic targets in WM and MZL. He describes the MYD88^wpk2] mutation which results in an upregulation of NFĸB signalling as well as the effect of HCK signalling on cell survival and proliferation. He explains the characteristics of the different BTK inhibitors (BTKis). Professor Treon elaborates on CXCR4 mutations in WM patients and the implication for treatment options with BTKis.