SummaryThe nucleotide sequences of the mouse, rat, and human cDNAs and genes that encode the fourth member of the Ras Guanine Nucleotide Releasing Protein (RasGRP) family of signaling proteins have been deduced. RasGRP4 is a mast cell (MC) restricted, cation‐dependent, guanine nucleotide exchange factor. It also is a diacylglycerol/phorbol ester receptor that plays a prominent role in dictating which protease and eicosanoid mediators are expressed in rat and human MC lines. RasGRP4 appears to act downstream of the surface receptor Kit/CD117 and upstream of the transcription factor MITF. Allelic variants of RasGRP4 have been identified, as well as functionally different isoforms that are the result of variable splicing of its gene. Earlier gene‐linkage studies revealed a site on chromosome 7A3‐B1 that controls intrinsic airway reactivity to methacholine in backcrossed C3H/HeJ and A/J mice. The 18‐exon mRasGRP4 gene resides on chromosome 7A3‐B1, and recent studies revealed that the MCs developed from the hyporesponsive C3H/HeJ mouse strain preferentially produce a defective isoform of mRasGRP4. These and other data suggest that RasGRP4 is of critical importance in MC development and that the expression of abnormal isoforms of the protein can lead to MC dysfunction.