Ibrutinib (Imbruvica, Pharmacyclics, Janssen) is the first-in-class irreversible inhibitor of Bruton's tyrosine kinase (BTK), which is positioned downstream of the BCR at the cell surface of normal and malignant B-cells. In 2013, the Food and Drug Administration (FDA) granted accelerated approval for the treatment of mantle-cell lymphoma (MCL), and in 2014 for chronic lymphocytic leukemia (CLL), in patients who had received at least one prior therapy. In 2015, the indication was extended to Waldenstrom macroglobulinemia (WM). In 2014, the European Medicines Agency (EMA) recognized monitored approval for adult patients with relapsed/refractory MCL, adult CLL patients after at least one prior therapy, and as first-line treatment in the presence of 17p deletion or TP53 mutation for subjects unsuitable for chemoimmunotherapy. In 2015, the indication was extended to WM patients who had received at least one prior therapy, or as first-line treatment for patients unsuitable for chemoimmunotherapy. The safety database for MCL consisted in 120 patients enrolled in study PCYC-1104-CA, integrated with nine patients from Study PCYC-04,753. Patients received 560 mg/d ibrutinib as continuous treatment, for a median exposure of 8.3 months. The initial safety evaluation (FDA) for CLL was based on 48 CLL/SLL (small lymphocytic lymphoma) patients of Study PCYC-1102-CA. These data were subsequently integrated with CLL/SLL patients from Study PCYC-04,753, for a total of 117 subjects exposed to ibrutinib for a median of 14.7 months; interim and crossover data from Phase III Study PCYC-1112 in 391 patients either exposed to ibrutinib (195 pts.) or ofatumumab (196 pts.) were also considered. The safety evaluation in WM patients was based on Phase II Study PCYC-1118E in 63 previously treated patients. Although showing differential incidences in some toxicities, the overall safety profile experienced in B-cell malignancies (CLL, MCL, WM) is substantially homogeneous and characterized by thrombocytopenia (TCP), diarrhea, anemia, neutropenia, fatigue, musculoskeletal pain/arthralgia, bruising, nausea, rash, and upper respiratory tract infection (URTI). Additional events of relevance are atrial fibrillation, bleeding, infections, cytopenia, pneumonitis, hypertension, tumor lysis syndrome (TLS), new primary malignancies (carcinoma), and potential embryo-fetal toxicity. Atrial fibrillation is among the more frequent adverse events (AEs) of concern evidenced across trials, especially in MCL treated in combination with rituximab.