Long-term immunity to many viral and bacterial pathogens requires CD8(+) memory T cell development, and the induction of long-lasting CD8(+) memory T cells from a naïve, undifferentiated state is a major goal of vaccine design. Formation of the memory CD8(+) T cell compartment is highly dependent on the early activation cues received by naïve CD8(+) T cells during primary infection. This review aims to highlight the cellularity of various niches within the lymph node and emphasize recent evidence suggesting that distinct types of T cell activation and differentiation occur within different immune contexts in lymphoid organs.