It has been suggested that ESP may have a subtle rather than an overt effect, and that the ability to perceive may be altered by the nature of the event being perceived. For example, some proponents of ESP put forward that predicting whether a loved one was just involved in a car crash might have a stronger effect than sensing which playing card was drawn from a deck, even though the latter is better suited for scientific studies. This, in part, is why scientists remain skeptical, although cases of ESP involving subjects who are familiar with each other have yielded results that would indicate a positive demonstration of the ability . There are no consistent and agreed-upon standards by which ESP powers may be tested, in the way one might test for, say, electrical current or the chemical composition of a substance. Often, when self-proclaimed psychics are challenged by skeptics and fail to prove their alleged powers, they assign all sorts of reasons for their failure, such as that the skeptic is affecting the experiment with "negative energy." This, and the practice of charlatanry in ESP and psychic circles, can cause scientists and rationalists to dismiss ESP claims out of hand.

There is some dispute over the interpretation of results obtained in scientific studies of ESP, as the most compelling and repeatable results are all small to moderate statistical results. Critics of ESP argue that the results are too small to be significant, while proponents of ESP argue that the results are consistent in numerous studies. The combined significance is large and considered to be further proof by proponents. That an inordinately large number of trials must be conducted to obtain statistically significant results is seen as a problem for verifying the legitimacy of ESP claims. However other areas of science, such as the medical field, rely heavily on this method of data collection. For example, the statistical results of the positive affect of aspirin on the heart are far less than many ESP results.

Claims of extra-sensory perception have been subjected to repeated criticism by mainstream scientists. Most of the criticism hinges on two major contentions: first, that studies which have shown evidence of ESP are almost always either anecdotal or plagued with methodological flaws which allowed cheating, and second, that the results of studies which are not flawed show no evidence of ESP.

An example of this case is that of an allegedly psychic dog in England named Jaytee, who his owners claim has an ability to sense when one of them was leaving work to come home (which he allegedly displayed by running out to the porch at that time). Biologist Rupert Sheldrake tested JayTee extensively, including more than 50 videotaped trials, and claimed that his tests had shown that the dog had ESP ability. Two skeptical scientists from the University of Hertfordshire, Richard Wiseman and Matthew Smith, then used Sheldrake's video camera setup, conducted 4 trials of their own, and claimed that the dog had no such ability. Wiseman and Smith concluded that while Jaytee made several trips to the window during the day, the action was more in response to having heard some kind of noise outside . However, Sheldrake believes the data they collected actually matched his own convincingly. Sheldrake has commented on the experiment conducted by Wiseman.

"As in my own experiments, he sometimes went to the window at other times, for example to bark at passing cats, but he was at the window far more when Pam was on her way home than when she was not. In the three experiments Wiseman did in Pam's parents' flat, Jaytee was at the window an average of 4% of the time during the main period of Pam's absence, and 78% of the time when she was on the way home. This difference was statistically significant" - Rupert Sheldrake