Through the last century, the increased greenhouse gases emissions altered the atmosphere’s composition and resulted to the phenomenon known as climate change. Climate change threatens the sustainability of the agricultural sector in the Mediterranean region. Droughts and extreme heat waves will probably become more frequent in the next few decades, thus maintaining sufficient yields in heat and drought susceptible major crops will be challenging. In Greece, cotton is of paramount economic importance. Besides the fact that it is regarded as the most significant fiber crop, Greece is the main cotton producer of the European Union. The aim of the present review was to examine the environmental factors that might affect cotton production in Greece and assess whether (or not) climate change has the potential to limit the productivity of this crop in the near future. According to the existing literature, cotton can adapt to the changing climate. Climate change-induced elevated CO2 levels and temperatures might even benefit cotton. The mitigation of the adverse effects of climate change is possible via the adaptation of site-specific agronomic practices. A simplistic framework, based on the literature and the goals of the European Union, that aims to the preservation of sufficient cotton yields in Greece is proposed in the present study.