Formaldehyde is one of the most comprehensively studied chemicals, with over 30 years of research focused on understanding the development of cancer following inhalation. The database has been reviewed by multiple authoritative bodies, focusing on upper respiratory tract cancer and leukemia to characterize the potential for carcinogenicity. The causal conclusions regarding the potential for leukemia are largely based on the epidemiological literature, with little consideration of the cancer bioassay and mechanistic research, which challenge causality attributed to the epidemiological results. Recent reanalyzes of the epidemiological literature have also raised significant questions related to the identified associations between formaldehyde and leukemia. Because of this, considerable scientific debate and uncertainty remains on whether there is a causal association between formaldehyde exposure and leukemia. Further complexity in evaluating this association is related to the endogenous production of formaldehyde. Multiple modes of action (MoA) have been proposed for development of leukemia following formaldehyde exposure that include untested hypotheses of direct or indirect toxicity to the target cell population. While US EPA evaluated potential modes of action for leukemia in 2010, this evaluation was not in a structured evidence framework. Additional research key to the question of causality has been conducted since that evaluation in response to comments from the National Academy of Sciences that raised significant questions concerning any causal association between leukemia and formaldehyde exposure. The available evidence relevant to evaluating the proposed MoAs for leukemia following formaldehyde exposure is organized in the IPCS MoA Framework, which provides a structured framework for evidence integration, using modified Bradford Hill criteria in determining the biological plausibility of causality. The integration of the available evidence clearly highlights the limited amount of data that support any of the proposed MoAs and demonstrates the significant amount of research that does not support a causal association between formaldehyde exposure and leukemia. The result is a lack of confidence in any of the proposed MoAs, increasing confidence in the conclusion that there is a lack of biological plausibility for a causal association between formaldehyde exposure and leukemia.