B-cell depletion therapy continues to emerge as an important means of inducing remission for severe or treatment-resistant autoimmune diseases. Standard practices in flow cytometry for measuring B-cells in the peripheral blood typically confirms the absence of circulating B cells for around 6 to 12 months after treatment with rituximab. However, more sensitive testing using minimal residual disease protocols reveals B-cell depletion is only partial in a significant number of treated patients, and that this correlates with clinical response to treatment. Subsequently, the reappearance of B cells is typically monitored in these patients, as disease relapse is associated with B-cell regeneration. In some conditions, including the devastating neurological disorder, neuromyelitis optica, the use of memory B cells as a marker for predicting disease relapse has emerged as a clinically useful test which alters the treatment strategy. I will discuss these issues and the impact on the diagnostic flow cytometry lab.