For asymptomatic patients with low-grade lymphoproliferative disorders and low tumor burden, watchful waiting represents a rational approach. For symptomatic patients or for those with high tumor burden, initial treatment is usually chemoimmunotherapy with an anti-CD20 monoclonal antibody (mo-Ab), most commonly Rituximab or Obinutuzumab plus an alkylator, such as bendamustine or chlorambucil and/or a pourine analog, such as fludarabine or cladribine. For the Refractory/Relapsed (RR) setting treatment options depend on patient's background, initial PFS and on various prognostic parameters. Newer anti-CD20 mo-Abs, such as Ublituximab appear equally effective, but have not yet been tested comparatively with the previous ones. Radioconjugates such as 90Y-ibritumomab tiuxetan and 131I-tositumomab are no more in broad use due to unpredicted myelotoxicity. The newer 90Y-epratuzumab tetratexan appears safe as consolidation following R-CHOP in DLBCL patients. Polatuzumab vedotin, Pinatuzumab vedotin and Tafasitamab targeting CD19 have mainly been used, combined with an anti-CD20 mo-Ab to treat RR-DLBCL with success, which render them candidates for indolent lymphomas also. BTK inhibitors represent one main treatment option, either as initial treatment or in the RR setting. Ibrutinib, the first in class drug, is used either alone or in combination with Mo-abs and/or alkylators. Acalabrutinib, already approved for CLL/SLL and MCL, is now being tested for other B-cell malignancies. Zanubrutinib, a newer analog not exhibiting some of ibrutinib's AE, has been approved for RR-MCL and is currently being evaluated alone or in combination with Mo-Abs, lenalidomide and other agents. Idelalisib, the first PI3K-inhibitor, the second family of highly used targeted agents, has been approved for CLL/SLL and FL. Duvelisib, Copanlisib and Umbralisib are newer agents coming up and are currently being tested usually in combination with mo-Abs or other agents. Bimiralisib, a dual PI3K/mTOR inhibitor is a promising agent still in phase I. Hepatotoxicity, the major AE of this class, is reversible and dose-dependent. The BCL2 inhibitor venetoclax, alone or combined with mo-Abs and/or bendamustine (BRVen) or with Ibrutinib (ongoing trial), is a breakthrough approach, being tested in several disease entities with impressive results. Bispecific antibodies engaging CD19 (Blinatumomab) or CD22 (Inotuzumab ozogamycin) to a T/NK-cell surface antigen have received approval for more aggressive B-cell lymphomas. Lenalidomide combined with Rituximab (R2) has demonstrated impressive results as initial treatment in FL and the newer cereblon-modifier Avadomide is now being tested in combination with Obinutuzumab in RR B-cell lymphomas of all types. Lenalidomide with Blinatumomab is also tested in an ongoing study. mTOR/NF-κB inhibitors (temsirolimus, everolimus) are not so effective as single agents but can be combined with various targeted and/or cytotoxic agents and construct synergistic regimens. Tazemetostat a novel EZH2 inhibitor recently received accelerated approval by FDA for patients with RR-FL and EZH2 gene mutations, following the results of a phase-II study. Combinations of this drug with other agents are also expected. Immune check point inhibitors (Nivolumab, Pemprolizumab, Atezolizumab) are promising as third line treatment and beyond. Other agents under investigation include the inhibitor of nuclear export selinexor, the SYK inhibitor entospletinib, the dual SYK/JAK inhibitor certulatinib and the CDK inhibitors flavopiridol and dinaciclib.