Recent research on hematological malignancies has shown that malignant cells often co-opt physiological pathways to promote their growth and development. Bone marrow homeostasis requires a fine balance between cellular differentiation and self-renewal; cell survival and apoptosis; and cellular proliferation and senescence. The Ras/Raf/MEK/ERK pathway has been shown to be important in regulating these biological functions. Moreover, the Ras/Raf/MEK/ERK pathway has been estimated to be mutated in 30% of all cancers, thus making it the focus of many scientific studies which have lead to a deeper understanding of cancer development and help to elucidate potential weaknesses that can be targeted by pharmacological agents [1]. In this review, we specifically focus on the role of this pathway in physiological hematopoiesis and how augmentation of the pathway may lead to hematopoietic malignancies. We also discuss the challenges and success of targeting this pathway.