Immunochemotherapy has long been the backbone of all treatment for B‑cell non-Hodgkin lymphoma. These therapies led to long-term disease control or even cure for some patients. However, these treatments also caused—sometimes severe—toxicities and deterioration of the quality of life. Novel agents targeting the B‑cell-receptor pathway and bcl2 have made great inroads in the treatment of mature lymphoid neoplasms. These new agents present themselves with a wide variety of new toxicities, which have to be taken into account when being administered to our patients. Hematological toxicities are very common. All new agents lead to various levels of immune suppression or immune modulation, which is often not easily quantifiable. Opportunistic infections such as progressive multifocal leukoencephalopathy, pneumocystis pneumonia, other mycotic infections, cytomegalovirus infections and pneumocystis pneumonia have been described, sometimes with fatal outcome. Ibrutinib shows increased risk of atrial fibrillation. It also increases the risk of bleeding, making the proper anticoagulatory management of patients developing atrial fibrillation under treatment a challenge. Idelalisib causes severe, sometimes fatal immune-mediated end-organ toxicities, especially colitis, pneumonitis, and transaminitis. Copanlisib leads to metabolic changes, namely episodes of hyperglycemia and arterial hypertension. Venetoclax has caused clinically significant tumor lysis syndrome. The introduction of a prolonged ramp-up phase of step wise dose escalation has decreased the rate of clinically significant tumor lysis syndrome. The drug also causes high rates of hematological toxicities, especially neutropenia.