**1. Introduction**

The RAS/RAF/MEK/ERK signalling cascade, also known as the MAPK (mitogen-activated protein kinase) pathway, is involved in cell proliferation, differentiation, survival and apoptosis [1]. It receives input from multiple sources including internal metabolic stress and DNA damage pathways and altered protein concentrations as well as through signalling from external growth factors, cell-matrix interactions and communication from other cells [2]. This allows for a nodal point for therapeutic targeting, however, dysregulation of this pathway can also increase malignant behaviour [3].

Multiple signals activate RAS (KRAS, NRAS and HRAS), a family of GTPases. This, in turn, activates downstream RAF protein kinases (ARAF, BRAF and CRAF). The dominant substrates of RAF kinases are the MAPK/ERK kinases, MEK1 and MEK2. ERKs phosphorylate a variety of substrates, including multiple transcription factors that regulate several key cellular activities (**Figure 1**).

Mutations in RAS and RAF are the most common oncogenes in human cancer [4]. The focus of this chapter will be on BRAF mutations in colorectal cancer, in particular the V600E mutation, the clinical significance, molecular and clinical pathogenesis as well as treatment, now and into the future.
