Close physical proximity between mast cells and T cells has been demonstrated in several human conditions. We have identified and characterized a novel mast cell activation pathway initiated by contact with T cells, and showed that this pathway is associated with cytokine release. It has been shown recently that Ras is activated in this pathway. Thus, in the present study we further explore the downstream events associated with Ras activation and cytokine release in human mast cells stimulated by contact with T cells. ERK activation in human mast cells stimulated by either contact with T cells or by crosslinking the FC epsilon receptor was studied. Photobleaching experiments were used to study ERK localization. Enzyme linked immunosorbent assay was used to study the cytokine release by human mast cells. We show that stimulation of human mast cells by contact with activated T cells results is sustained ERK activation. Furthermore, sustained ERK activation in these cells is associated with increased dwell time at the nucleus and with IL-8 release. Interestingly, when mast cells were stimulated by crosslinking the FC epsilon receptor I, ERK activation was transient. ERK activation was associated with a shorter dwell time at the nucleus and with TNF-alpha release. Thus, retaining ERK in the nucleus might be a mechanism utilized by human mast cells to generate different cytokines from a single signaling cascade.