The past few decades have delivered significant improvements in diagnosis and treatment of cancer, however, despite these improvements cancer continues to be a major global health issue requiring the urgent development of new strategies for treatment. Stress granules are cytoplasmic structures that triage gene expression in response to environmental stresses, including chemotherapies, and have been implicated in the development of drug resistance. One novel approach to developing a new anti-cancer strategy involves inhibiting stress granules with compounds derived from natural products. In a previous rapid screen, a subset of 132 compounds from the Davis Open Access Natural Product Library was screened using a stress granule inhibition assay and provisionally one hit was identified which was the known marine sponge-derived metabolite, psammaplysin F. Using cell based assays psammaplysin F was assessed to determine whether it could inhibit the formation of stress granules after exposure to sodium arsenite in Vero, HEK293 MCF7, T47D, HeLa and MCF7MDR cells by analysing the number of stress granules using high content imaging. A significant reduction in the number of stress granules was observed and subsequent analysis by western blot revealed that treatment with psammaplysin F decreased levels of phosphorylated eIF2α. Combinational studies in MCF7, HeLa and MCF7MDR cells revealed that psammaplysin F increased the efficacy of bortezomib and sorafenib and a synergistic effect was observed in vitro. Stress granules appear to be one tool in a battery of responses that cancer cells can exploit to elicit drug resistance. Disrupting stress granule formation by use of orally available drugs presents a potential mechanism to restore drug efficacy. The work presented here provides evidence that small molecules derived from nature, such as psammaplysin F, can prevent the formation of stress granules and therefore may represent a useful strategy to improving drug efficacy.