Efforts to develop a new, more effective vaccine for tuberculosis have been hampered by a lack of understanding of what constitutes a protective memory immune response. While interferon gamma production by CD4(+) T cells after vaccination is commonly used as a surrogate of protective memory immunity, its use in this regard appears to have little predictive value. We argue that this is due to the different requirements for interferon gamma-mediated protection in the primary response versus the memory recall response. In this review, we present evidence that suggests memory CD4(+) T cells can protect against tuberculosis in the absence of interferon gamma, and discuss potential mechanisms that may be involved such as IL-17 and regulatory T cells. A comprehensive understanding of the requirements for protective memory immunity to tuberculosis is essential for the development of an effective vaccine.