Development of tolerance to the effects of the anticholinesterase, di-isopropylfluorophosphonate (DFP), on core body temperature, a simple operant drinking response, and an operant fixed ratio lever-press response has been studied in the males and females of the S14 and S15 generations of two lines of rats genetically selected for their differences in sensitivity to DFP. For temperature measurement, males and females of the Flinders-resistant line (R-line) developed tolerance quicker than did the males and females of the Flinders-sensitive line (S-line). For the operant drinking response, females of both lines were tolerant after the third injection, while resistant males were tolerant only after the seventh injection and sensitive males were not completely tolerant at the conclusion of the experiment. For the operant fixed ratio lever-press responding all groups were tolerant after the second injection. These findings indicate that the development of tolerance to DFP can be influenced by the genetic background, the sex of the organism and the nature of the behaviour being measured, suggesting that several mechanisms may underlie development of tolerance to this agent.