Current therapies for immune-mediated diseases, such as rheumatoid arthritis and MS, could represent the proverbial bird in the hand – a known entity, yet limited in potential. Emerging biologic therapeutics for these diseases carry with them the potential for known as well as unknown adverse effects. Alemtuzumab, a biologic that depletes leukocytes, shows great promise for the treatment of MS. However, a significant number of patients develop autoimmunity after treatment, raising the level of caution for the use of this drug. In this issue of the JCI, Jones et al. describe a link between IL-21 levels and alemtuzumab-associated autoimmunity (see the related article beginning on page 2052). They show that proliferation of lymphocytes in those patients with autoimmunity is higher than in those without autoimmunity and suggest that the lymphopenia-driven proliferation of T cells, in combination with higher IL-21 levels, results in autoimmunity. This study helps inspire new enthusiasm for making a grab for the proverbial two birds in the bush – representing undiscovered therapies – with greater confidence.