The important role of BTK pathway in many processes associated with malignancies has been undoubtedly proven. BTK was linked to many B cell malignancies. Studies and trials attempting to find ways to exploit the BTK in B cell malignancies lead to the approval of many BTK inhibitors like Ibrutinib and Acalabrutinib in many B cell malignancies. An important group of patients benefiting from these agents were the relapsed/ refractory group (R/R) amongst other indications for various malignancies including WM, CLL/SLL, MCL and MZL. Although BTK inhibitors have revolutionized the treatment of many malignant diseases, toxicities and resistance cause decreased benefit/risk ratio and may lead to discontinuation of therapy. Toxicities have ranged from minimal that could be managed in different ways to life threatening that requires discontinuation. As a result, developing BTK inhibitor with a better safety profile have become one of the corner stones in this field along with investigating other malignancies that can benefit from this therapy option.