Host factors are crucial in determining the outcome of viral infection. As obligate intracellular pathogens, viruses are highly dependent on numerous cellular proteins and processes, and also must evade multiple antiviral defense mechanisms. Since viral pathogens represent a significant threat both to human health and agriculture, a better understanding of these interactions could facilitate the treatment of viral infections and provide novel targets for therapeutics. In particular, Poxviruses include medically important human pathogens yet little is known about the specific cellular factors essential for their replication. To identify genes essential for vaccinia infection, I used high-throughput RNA interference to screen Drosophila kinases and phosphatases. I identified seven genes including the three subunits of AMPK as promoting vaccinia infection. AMPK facilitated infection both in insect and mammalian cells. I found that AMPK is required for macropinocytosis, a major endocytic entry pathway for vaccinia. Furthermore, AMPK contributes to other actin-dependent cellular processes including lamellipodia formation and wound healing, independent of the known AMPK activators LKB1 and CaMKK. Therefore, AMPK plays a highly conserved role in poxvirus infection and actin dynamics independent of its role as an energy regulator. This led me to investigate the role of AMPK in other viral infections, including human arthropod-borne viral pathogens. Surprisingly I found that AMPK expression and activation restricts infection of the Bunyavirus Rift Valley Fever Virus (RVFV) in an LKB1-dependent manner. RVFV like other RNA viruses manipulates cellular membranes to form vesicle-like structures that support the viral replication complex in a process dependent on de novo fatty acid synthesis. I found that AMPK activation potently inhibits acetyl Co A carboxylase, crucial in fatty acid synthesis, leading to decreased levels of cellular lipids. Bypassing fatty acid synthesis by treating cells with palmitate, the first product of fatty acid synthesis rescued infection, demonstrating that AMPK restricts RVFV by inhibiting fatty acid synthesis. Additional RNA viruses that require membrane proliferations including the Togavirus Sindbis and the Alphavirus Vesicular Stomatitis Virus were also restricted by AMPK. AMPK is likely a component of the intrinsic innate immune response against RNA viruses, and may provide a target for broadly anti-viral therapeutics.