For centuries Amazonia has held the Western scientific and popular imagination as a primordial forest, only minimally impacted by small, simple and dispersed groups that inhabit the region. Studies in historical ecology refute this view. Rather than pristine tropical forest, some areas are better viewed as constructed or ‘domesticated’ landscapes, dramatically altered by indigenous groups in the past. This paper reviews recent archaeological research in several areas along the Amazon River with evidence of large pre-European (ca 400–500 calendar years before the present) occupations and large-scale transformations of forest and wetland environments. Research from the southern margins of closed tropical forest, in the headwaters of the Xingu River, are highlighted as an example of constructed nature in the Amazon. In all cases, human influences dramatically altered the distribution, frequency and configurations of biological communities and ecological settings. Findings of historical change and cultural variability, including diverse small to medium-sized complex societies, have clear implications for questions of conservation and sustainability and, specifically, what constitutes ‘hotspots’ of bio-historical diversity in the Amazon region.