In Britain and Ireland, the eastern gray squirrel is not regulated by natural predators,[39] other than the European pine marten, which is generally absent from England and Wales.[40] This has aided its rapid population growth and has led to the species being classed as a pest. Measures are being devised to reduce its numbers, including one plan for celebrity television chefs to promote the idea of eating the squirrels.[41] In areas where relict populations of red squirrels survive, such as the islands of Anglesey and Brownsea, programs exist to eradicate gray squirrels in an effort to allow red squirrel populations to recover.[42]

Although complex and controversial, the main factor in the eastern gray squirrel's displacement of the red squirrel is thought to be its greater fitness, hence a competitive advantage over the red squirrel on all measures.[43] The eastern gray squirrel tends to be larger and stronger than the red squirrel and has been shown to have a greater ability to store fat for winter. The squirrel can, therefore, compete more effectively for a larger share of the available food, resulting in relatively lower survival and breeding rates among the red squirrel. Parapoxvirus may also be a strongly contributing factor; red squirrels have long been fatally affected by the disease, while the eastern gray squirrels are unaffected, but thought to be carriers – although how the virus is transmitted has yet to be determined. However, several cases of red squirrels surviving have been reported, as they have developed an immunity – although their population is still being massively affected. The red squirrel is also less tolerant of habitat destruction and fragmentation, which has led to its population decline, while the more adaptable eastern gray squirrel has taken advantage and expanded.

Similar factors appear to have been at play in the Pacific region of North America, where the native American red squirrel has been largely displaced by the eastern gray squirrel in parks and forests throughout much of the region.
Ironically, "fears" for the future of the eastern gray squirrel arose in 2008, as the melanistic form (black) began to spread through the southern British population.[44][45] In the UK, if a "grey squirrel" (eastern gray squirrel) is trapped, under the Wildlife and Countryside Act 1981, it is illegal to release it or to allow it to escape into the wild; instead, it should be humanely destroyed.[46]