During evolution, plants have developed mechanisms to cope with and adapt to different types of stress, including microbial infection. Once the stress is sensed, signaling pathways are activated, leading to the induced expression of genes with different roles in defense. Mosses (Bryophytes) are non-vascular plants that diverged from flowering plants more than 450 million years ago, allowing comparative studies of the evolution of defense-related genes and defensive metabolites produced after microbial infection. The ancestral position among land plants, the sequenced genome and the feasibility of generating targeted knock-out mutants by homologous recombination has made the moss Physcomitrella patens an attractive model to perform functional studies of plant genes involved in stress responses. This paper reviews the current knowledge of inducible defense mechanisms in P. patens and compares them to those activated in flowering plants after pathogen assault, including the reinforcement of the cell wall, ROS production, programmed cell death, activation of defense genes and synthesis of secondary metabolites and defense hormones. The knowledge generated in P. patens together with comparative studies in flowering plants will help to identify key components in plant defense responses and to design novel strategies to enhance resistance to biotic stress.