Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer of lymphocytes, and a large proportion of patients are either unresponsive or develop resistance towards R-CHOP--the standard treatment regimen. Can one treatment then benefit all patients? In a review published in Chinese Medical Journal, researchers comprehensively summarize the molecular pathways and tumor microenvironment alterations across DLBCL that contribute to drug resistance and suggest a tailored treatment approach by screening for predictors of drug resistance.