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The Western honey bee (<i>Apis</i> <i>mellifera</i> L., Hymenoptera: Apidae) is a species of crucial economic, agricultural and environmental importance. In the last ten years, some regions of the world have suffered from a significant reduction of honey bee colonies. In fact, honey bee losses are not an unusual phenomenon, but in many countries worldwide there has been a notable decrease in honey bee colonies. The cases in the USA, in many European countries, and in the Middle East have received considerable attention, mostly due to the absence of an easily identifiable cause. It has been difficult to determine the main factors leading to colony losses because of honey bees' diverse social behavior. Moreover, in their daily routine, they make contact with many agents of the environment and are exposed to a plethora of human activities and their consequences. Nevertheless, various factors have been considered to be contributing to honey bee losses, and recent investigations have established some of the most important ones, in particular, pests and diseases, bee management, including bee keeping practices and breeding, the change in climatic conditions, agricultural practices, and the use of pesticides. The global picture highlights the ectoparasitic mite <i>Varroa destructor</i> as a major factor in colony loss. Last but not least, microsporidian parasites, mainly Nosema ceranae, also contribute to the problem. Thus, it is obvious that there are many factors affecting honey bee colony losses globally. Increased monitoring and scientific research should throw new light on the factors involved in recent honey bee colony losses. The present review focuses on the main factors which have been found to have an impact on the increase in honey bee colony losses.