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Marginal zone lymphomas (MZLs) are a heterogeneous group of rare, typically indolent B-cell lymphoid hematologic disorders where the B-cell receptor (BCR) and its downstream signaling pathways, including Bruton’s tyrosine kinase (BTK), play a central role in the pathophysiology of these hematologic disorders and are major targets for various drug treatments. Targeting the BCR and its downstream kinases such as BTK is critical for the control and inhibition of cell survival. While first-line treatments remain standard, often relying on immunotherapy or immunochemotherapy, relapse treatments have evolved in recent years, with targeted therapies taking the lead, foremost among which are Bruton’s tyrosine kinase inhibitors (BTKis). Ibrutinib is the first of its class to demonstrate efficacy but lacks marketing authorization (MA). Second-generation molecules like zanubrutinib (which has MA but is yet to be covered by the French health insurance system) or acalabrutinib (which does not have MA for this indication) appear to be more effective, offering deeper and more prolonged responses, as well as a more favorable toxicity profile.