Neurotrophins interact with two distinct classes of cell-surface receptors, the Trk receptor tyrosine kinase family and the common neurotrophin receptor p75NTR. For many years, the biological role of p75NTR remained obscure, being relegated to modulating Trk binding of neurotrophins. Recently, the importance of p75NTR as a signaling receptor in itself has become increasingly clear. The signals initiated by p75NTR are likely to be as complex as those for the Trk family and probably depend on the cell system in which such signaling is being studied. In this study, all members of the neurotrophin family were demonstrated to be capable of stimulating p75NTR-mediated activation of the mitogen-activated protein kinase (MAPK) family (ERK1,2). This activation is rapid and transient, peaking at 5–15 min, depending on the cell system. The classical MAPK cascade consists of the reaction series Ras-Raf-MEK-MAPK. The p75NTR-induced MAPK activation is MEK dependent but Raf independent. This result implies that neurotrophin activation of p75NTR results in some cascade (as yet unknown) that bypasses Raf and converges on MEK to result in activation of MAPK. This activated MAPK is then able to translocate to the nucleus. The effect of this MAPK activation on cell survival is dependent on cell type. These results support the concept that signaling from the p75NTR receptor is more diverse and extensive than previously believed. © 2003 Wiley-Liss, Inc.