An important challenge in biology is to discover a principle that determines individual phenotypic differences within species. To unravel this principle, we investigated the growth rates of diverse natural isolates as well as a large cross between two representative strains of Saccharomyces cerevisiae. We found that each strain has the acquired fitness trade-off between normal and stressful conditions. By analyzing gene expression profiles, we identified two well-conserved co-expression gene modules whose expression levels are related to the fitness trade-off. We found that the two gene modules determine the fitness advantage in normal and stressful conditions, and thereby are related to growth preference and stress resistance, respectively. Moreover, we found that the genetic variation of RAS/cAMP/PKA signaling pathway might be the potential route of regulating the fitness trade-off. Intriguingly, we found that the fitness trade-off of yeast can account for the different drug resistance of various cancer cell lines. Our experiments showed that we can reduce the drug resistance of cancer cells regardless of different genetic backgrounds, cell types, and anti-cancer drugs. Together, we suggest that the fitness trade-off between growth preference and stress resistance might be the evolutionary principle determines the distinct individual growth phenotype within species.