ABSTRACT BRAF is a notable oncoprotein within the MAPK signaling pathway, which is a pathway that sends a signal from the surface of a cell to the nucleus of a cell via phosphorylation cascades. This pathway regulates cell growth, differentiation, and survival. BRAF is known to be mutated in about 50% of melanomas, and less frequently in a wide variety of other cancers, making BRAF a bona-fide target for therapy. In melanoma, a single V600E activation segment mutation (BRAFV600E) accounts for ~90% of BRAF mutant malignant tumors. BRAFV600E selective inhibitors, such as vemurafenib, extend the survival of patients in the clinic, however most patients develop drug resistance and progress at a median of 6 months. One mode of resistance is “paradoxical activation” of RAF heterodimers. In this mechanism, a drug-bound BRAF protomer dimerizes with either BRAFWT or CRAFWT, allosterically stimulating kinase activity and leading to hyper-activation of the MAPK pathway. The first part of this thesis involves my efforts to develop bivalent BRAF inhibitors to target paradoxical activation of active RAF dimers. We successfully chemically linked two BRAFV600E selective vemurafenib inibitors and found that this bivalent inhibitor stabilized an inactive face-to-face BRAF dimer conformation. We then extended this strategy to pan-RAF inhibitor TAK632 to target BRAFWT and CRAFWT in cells. Interestingly, this bivalent molecule was unable to “trap” two BRAF molecules in the same face-to-face conformation as the bivalent vemurafenib inhibitor, but also uncovered that the monovalent TAK632 depends on induction of active conformation BRAF dimers to be able to potently inhibit RAF. The last part of this thesis involved the development of a high throughput screen to discover novel inhibitors that can disrupt the complex between BRAF and its downstream substrate MEK. We were able to design a high throughput TR-FRET assay to identify 15 novel inhibitors that can inhibit BRAF/MEK dimerization. Together, our studies identify novel RAF dimer inhibitors that can be used as chemical probes to further understand BRAF signaling through RAF dimerization in melanoma and other BRAF-related cancers. These studies also highlight a novel method of targeting paradoxical activation and RAF dimerization for melanoma therapy.