The newly identified smoke hazard, thirdhand smoke (THS), has gained public attention in recent years but its health impact and biological effects are largely unknown. THS may be defined by ?the four Rs?: tobacco chemicals that remain, react, re-emit, and/or are resuspended long after active smoking has ceased. This review summarizes recent research progress in the effects of THS on genotoxicity, metabolism and early life development using cellular and animal models. We first reported that THS generated in laboratory systems caused significant DNA damage in human cell lines. Our finding that THS significantly induces oxidative base lesions has been confirmed in skin wounds of mice models exposed to THS. THS also induced metabolomic changes in human reproductive cell lines. Furthermore, we demonstrated that early exposure to THS not only negatively impacts body weight in both male and female mice, but also induces persistent changes to immunological parameters in peripheral blood in these mice. These results indicate that THS is genotoxic at realistic experimental doses and that there may be a window of susceptibility for some forms of cellular damage induced by THS.