There is a trend world-wide to grow crops in short rotation or in monoculture, particularly in conventional agriculture. This practice is becoming more prevalent due to a range of factors including economic market trends, technological advances, government incentives, and retailer and consumer demands. Land-use intensity will have to increase further in future in order to meet the demands of growing crops for both bioenergy and food production, and long rotations may not be considered viable or practical. However, evidence indicates that crops grown in short rotations or monoculture often suffer from yield decline compared to those grown in longer rotations or for the first time. Numerous factors have been hypothesised as contributing to yield decline, including biotic factors such as plant pathogens, deleterious rhizosphere microorganisms, mycorrhizas acting as pathogens, and allelopathy or autotoxicity of the crop, as well as abiotic factors such as land management practices and nutrient availability. In many cases, soil microorganisms have been implicated either directly or indirectly in yield decline. Although individual factors may be responsible for yield decline in some cases, it is more likely that combinations of factors interact to cause the problem. However, evidence confirming the precise role of these various factors is often lacking in field studies due to the complex nature of cropping systems and the numerous interactions that take place within them. Despite long-term knowledge of the yield-decline phenomenon, there are few tools to counteract it apart from reverting to longer crop rotations or break crops. Alternative cropping and management practices such as double-cropping or inter-cropping, tillage and organic amendments may prove valuable for combating some of the negative effects seen when crops are grown in short rotation. Plant breeding continues to be important, although this does require a specific breeding target to be identified. This review identifies gaps in our understanding of yield decline, particularly with respect to the complex interactions occurring between the different components of agro-ecosystems, which may well influence food security in the 21st Century.