The policies and actions that were enacted to colonize Indigenous Peoples in Canada have been described as constituting cultural genocide. When one considers the long-term consequences from the perspective of the social and environmental determinants of health framework, the impacts of such policies on the physical and mental health of Indigenous Peoples go well beyond cultural loss. This paper addresses the impacts of key historical and current Canadian federal policies in relation to the health and well-being of Indigenous Peoples. Far from constituting a mere lesson in history, the connections between colonialist policies and actions on present-day outcomes are evaluated in terms of transgenerational and intergenerational transmission processes, including psychosocial, developmental, environmental, and neurobiological mechanisms and trauma responses. In addition, while colonialist policies have created adverse living conditions for Indigenous Peoples, resilience and the perseverance of many aspects of culture may be maintained through intergenerational processes.