The Red Sea was the main route connecting Rome to India the East. Its main facilitator was Palmyra a major trading nation that had grown wealthy from its strategic position on the east-west overland trade road routes, specifically the trade networks linking Mesopotamia and the Persian Gulf to the Roman Empire. During the second and third centuries this started to change and an increasing number of Palmyrene traders moved away from the Persian Gulf and started to use the route via the Red Sea. This work looks at the evidence of trade in both areas and considers how and to what extent it changed. It considers archaeological and written evidence, such as ostraka found at the Red Sea port of Berenice showing names of Palmyran traders, as well as ancient literary testimony. To understand why this started to happen I will provide a historical context. This will describe Palmyra's situation as a client state of Rome and how it maintained its neutrality or not in the conflicts with Parthia. Additionally we shall examine the impact that periodic warfare between Rome and the Parthians/Sassanians had on the traditional Mesopotamian-Persian Gulf route that was utilised by many Palmyrene merchants. Such conflict notably become pronounced under the Antonine and Severan emperors.