Many different orders of magnitude are involved in the development of radiation-induced biological damage, both at a spatial level (from atomic dimensions to cellular and organ dimensions) and at a temporal level (from the 10−15 s of the physical interactions to the hours, and possibly years, of the biological processes). This chapter considers the very early events. The following aspects are treated: radiation interaction with matter; the Monte Carlo method; the track structure method, time evolution of the track, including the pre-chemical phase (radiolysis and radical production) and the chemical phase (diffusion and interaction with biological structures); the DNA damage; the microdosimetric approach; and the amorphous track approach. A final section is devoted to the criteria to integrate physical mechanistic investigations and approaches with a systems radiation biology approach.