Macrophomina phaseolina is a necrotrophic soil-borne fungal pathogen that causes a disease commonly known as charcoal rot. This fungus has the potential to infect over 500 different plant species worldwide including many important crops such as soybean, corn and sorghum. The fungal infection dramatically decreases the yield of a crop due to loss in biomass, low seed quality and plant death. Currently, there is not an effective method for controlling the disease, because knowledge about the pathogen, the development of the disease and how it interacts with the plant host is limited. Therefore, a study was proposed to investigate the interactions between M. phaseolina and the model legume Medicago truncatula, following a molecular genetics approach where the host genes involved in the disease development will be identified. We conducted a genetic screen in a mutant population of M. truncatula to look for strains that have altered susceptibility to M. phaseolina. The initial screen of 259 Tnt1 lines identified seven lines that showed altered susceptibility to M. phaseolina. However, the second screen did not corroborate the results that were first obtained, and none of the seven Tnt1 lines showed altered susceptibility to the fungus. In addition, we screened 174 M. truncatula wild type ecotypes. As was expected, these ecotypes did not show altered susceptibility to M. phaseolina. Finally, we examined the effects of phytohormones jasmonic acid (JA) and ethylene (ET) in M. truncatula when infected with the M. phaseolina. Our results indicated that JA and ET slightly increased the resistance of the plants to this fungal pathogen. This makes us think that the modification of JA or ET signaling pathways may improve plant resistance to M. phaseolina. This study provides a basis for a further investigation of molecular interactions between M. phaseolina and its plant hosts.