The development of B-cell lymphomas is an intricate interplay among various pathogenic factors, leading to a multi-step process, encompassing various stages of B-cell maturation. Besides genetic abnormalities, a variety of environmental and microbial factors, as well as disproportional immune-regulatory processes lead to the malignant transformation. Yet, little is known about the exact chain of events, which lead from the physiological polyclonal B-cell activation as a response to exogenous antigens through oligoclonality to a monoclonal, uncontrolled, malignant B-cell proliferation. The aim of the present review was to summarize the potential harmful steps in the development of B-cell lymphomas, according to conventional and novel theories, and to depict therapeutic regimens presently in use as well as to envision future drug developments, beneficial in the battle against this lymphoid malignancy.