The mitogen-activated protein kinase (MAPK) signaling pathway is activated in response to a variety of extracellular stimuli such as growth factor stimulation. The best-characterized MAPK pathway involves the sequential activation of Raf, MEK and ERK proteins, capable of regulating the gene expression required for cell proliferation. Binding to specific lipids can regulate both the subcellular localization of these MAPK signaling proteins as well as their kinase activities. More recently it has become increasingly clear that the majority of MAPK signaling takes place intracellularly on endosomes and that the perturbation of endocytic pathways has dramatic effects on the MAPK pathway. This review highlights the direct effects of lipids on the localization and regulation of MAPK pathway proteins. In addition, the indirect effects lipids have on MAPK signaling via their regulation of endocytosis and the biophysical properties of different membrane lipids as a result of growth factor stimulation are discussed. The ability of a protein to bind to both lipids and proteins at the same time may act like a "ZIP code" to target that protein to a highly specific microlocation and could also allow a protein to be "handed off" to maintain tight control over its binding partners and location.