In Mediterranean and north-African regions, cultural trajectories have shown trends sometimes coincident with climatic changes. The mid Holocene was a period of intense changes in climate, and in environmental and cultural systems. This paper reports pollen and charcoal studies from these areas aiming at presenting how impressive cultural changes frequently coincided with critical climate oscillations. Three of the main dry events of key relevance for climatic—cultural changes were selected to discuss this topic: c. 8200 cal. yr BP, c. 6000 cal. yr BP, and c. 4200 cal. yr BP. Five examples from on-site case studies were reported: (1) Wadi Teshuinat area (Fezzan, Libya, Central Sahara); (2) Benzù cave (Ceuta mountains, Spain, NW Africa); (3) La Vaquera Cave (Central System, Spain); (4) Terramara di Montale (Po Plain, Northern Italy); (5) Arslantepe (Eastern Anatolia, Turkey). Their archaeobotanical record helps to recognise and date human presence and activity in different territories. In these examples, anthropogenic signals and comparisons with other sites could be useful to distinguish climate signal from human impact in pollen records. Charcoals are evidence of human activity in cases which are not shown by pollen. Overexploitation of thinned plant resources, including overgrazing, accelerated the evolution towards xeric conditions during drying climatic phases. Humans enforced the aridity crisis and enhanced its signal in palaeoclimatic records. Sometimes, changing exploitation strategies and movements led to the onset of new cultures. Nevertheless, the onset and decline of a culture are very different critical phases, and different agents must have been involved in their occurrence. The Bronze Age marked the environment more than the Neolithic, probably because there is a relation between improvements in knowledge, cultural changes and the evolution of complex forms of land exploitation.