The mitogen-activated protein kinase (MAPK) pathway is essential for cellular proliferation, growth, and survival. BRAF mutations can cause constitutive activation of this pathway, leading to uncontrolled cellular growth and carcinogenesis. Inhibiting BRAF and MEK has been shown to be effective in controlling tumor growth and proliferation. Over the past decade, several BRAF and MEK inhibitors have been investigated for various cancers, leading to FDA approvals for melanoma, non-small cell lung cancer, anaplastic thyroid cancer, colorectal cancer, and other cancers. This review discusses the development of BRAF and MEK inhibitors from melanoma to tumor-agnostic indications, novel drugs, challenges, future directions, and their importance in personalized medicine. The MAPK pathway includes RAS, RAF, MEK, and ERK. BRAF is a RAF protein kinase with three isoforms. BRAF and MEK inhibitors target the MAPK pathway to inhibit cancer growth. BRAF inhibitors include vemurafenib, dabrafenib, and encorafenib, while MEK inhibitors include trametinib, cobimetinib, and binimetinib. These inhibitors have been tested in various cancers, including melanoma, gastrointestinal cancers, non-small cell lung cancer, hematological malignancies, and central nervous system tumors. BRAFV600E is the most common BRAF mutation, and BRAF/MEK inhibitors have shown efficacy in melanoma, colorectal cancer, and other cancers. However, resistance mechanisms, such as mutations in NRAS or KRAS, can lead to treatment failure. Combination therapies with immunotherapy have been explored to overcome resistance and improve outcomes. The FDA has approved several BRAF/MEK inhibitor combinations for various cancers, highlighting their importance in personalized medicine. Challenges include managing toxicities and developing more effective treatments. Future research focuses on improving efficacy, reducing side effects, and expanding indications for these inhibitors.The mitogen-activated protein kinase (MAPK) pathway is essential for cellular proliferation, growth, and survival. BRAF mutations can cause constitutive activation of this pathway, leading to uncontrolled cellular growth and carcinogenesis. Inhibiting BRAF and MEK has been shown to be effective in controlling tumor growth and proliferation. Over the past decade, several BRAF and MEK inhibitors have been investigated for various cancers, leading to FDA approvals for melanoma, non-small cell lung cancer, anaplastic thyroid cancer, colorectal cancer, and other cancers. This review discusses the development of BRAF and MEK inhibitors from melanoma to tumor-agnostic indications, novel drugs, challenges, future directions, and their importance in personalized medicine. The MAPK pathway includes RAS, RAF, MEK, and ERK. BRAF is a RAF protein kinase with three isoforms. BRAF and MEK inhibitors target the MAPK pathway to inhibit cancer growth. BRAF inhibitors include vemurafenib, dabrafenib, and encorafenib, while MEK inhibitors include trametinib, cobimetinib, and binimetinib. These inhibitors have been tested in various cancers, including melanoma, gastrointestinal cancers, non-small cell lung cancer, hematological malignancies, and central nervous system tumors. BRAFV600E is the most common BRAF mutation, and BRAF/MEK inhibitors have shown efficacy in melanoma, colorectal cancer, and other cancers. However, resistance mechanisms, such as mutations in NRAS or KRAS, can lead to treatment failure. Combination therapies with immunotherapy have been explored to overcome resistance and improve outcomes. The FDA has approved several BRAF/MEK inhibitor combinations for various cancers, highlighting their importance in personalized medicine. Challenges include managing toxicities and developing more effective treatments. Future research focuses on improving efficacy, reducing side effects, and expanding indications for these inhibitors.