Cell transformation is often a result of constitutive activation of genes in signaling pathways that regulate cell proliferation and differentiation. Indeed, the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway is constitutively activated in a large number of cancers. The extent to which a single-gene mutation can alter cell fate, however, remains questionable. In vitro studies have addressed this issue, but organs are comprised of multiple cell types, and in vitro models often poorly approximate these interactions. In response to these limitations, cell-type specific mouse models have been generated as a means to examine the effect of altering a single element of the MAPK pathway in vivo. This review summarizes data from transgenic murine and human tissue models expressing constitutive active forms of MEK1.