The ideal treatment of patients with primary membranous nephropathy (MN) and persistent nephrotic syndrome (NS) is still a matter of debate. This is a major issue since these patients may progress to end-stage kidney disease (ESKD) in 5-10 years. Steroids, alkylating agents, and calcineurin inhibitors have been suggested to achieve NS remission and prevent ESKD in this population. Treatment benefits, however, are uncertain and are often offset by serious adverse events (SAEs). Evidence that B cells play a crucial role in the pathogenesis of the disease, both as precursors of autoantibody-producing cells and as antigen-presenting cells, provided the background for explorative studies testing the role of B cell-depletion therapy with the monoclonal antibody rituximab. This approach aimed at selectively inhibiting disease mechanisms without the devastating consequences of unspecific immunosuppression. Finding that rituximab safely ameliorated NS in 8 patients with primary MN fueled a series of observational studies that uniformly confirmed the safety/efficacy profile of rituximab in this context. Although head-to-head comparisons in randomized clinical trials are missing, comparative analyses between series of homogeneous patient cohorts clearly show at least similar efficacy of rituximab as compared to steroid plus alkylating agents. Moreover, data confirm the dramatically superior safety profile of rituximab that actually appears to be associated with a rate of SAEs even lower than that observed with conservative therapy. Rituximab is also effective in patients resistant to other treatments and its cost-effectiveness is further increased when treatment is titrated to circulating B cells. Recently identified pathogenic antibodies against the M type phospholipase A₂ receptor will likely provide a novel tool to monitor disease activity and drive rituximab therapy, at least in a subset of patients. Newly developed anti-CD20 antibodies could represent a valuable option for those who fail rituximab therapy. Steroids, alkylating agents, and calcineurin inhibitors should likely be abandoned.