Significant advances have been made in understanding mechanisms of plant defense against biotrophic and necrotrophic pathogens. Whole-genome sequencing of these pathogens has uncovered the genetic underpinnings of the distinct and common virulence and defense mechanisms. Necrotrophic pathogens produce toxins, necrosis-inducing proteins, secondary metabolites, and hydrolytic enzymes, and their virulence generates endogenous plant peptides. The recognition of these factors triggers broad-spectrum quantitative resistance. Resistance to specialist, host-specific, toxin-producing pathogens is mediated by the absence of host susceptibility proteins, including nucleotide-binding leucine-rich repeats (NLRs), or by detoxification mechanisms. Biotrophic pathogens utilize distinct virulence strategies, and NLR proteins are critical determinants of resistance, interacting synergistically with other quantitative resistance factors. However, NLRs are ineffective against necrotrophs, which exploit canonical immune responses to establish and promote disease. Immune responses such as hypersensitive cell death and the production of reactive oxygen species and accumulation of hormones exhibit distinct or complex roles in defense against biotrophic and necrotrophic pathogens. Lately, the microbiome has become instrumental in uncovering novel pathogen resistance mechanisms. However, further studies are needed to understand the genes involved in recruiting defense-promoting microbes and their impact on pathogens with distinct virulence. Overall, a comprehensive understanding of mechanisms of resistance to biotrophic and necrotrophic pathogens is crucial for activating or suppressing appropriate host responses.