The complexity of interactions of electromagnetic fields up to 1012 Hz with the ions, atoms, and molecules of biological systems has given rise to a large number of established and proposed biophysical mechanisms applicable over a wide range of time and distance scales, field amplitudes, frequencies, and waveforms. This review focuses on the physical principles that guide quantitative assessment of mechanisms applicable for exposures at or below the level of endogenous electric fields associated with development, wound healing, and excitation of muscles and the nervous system (generally, 1 to 102 V m−1), with emphasis on conditions where temperature increases are insignificant (←1 K). Experiment and theory demonstrate possible demodulation at membrane barriers for frequencies ≤10 MHz, but not at higher frequencies. Although signal levels somewhat below system noise can be detected, signal-to-noise ratios substantially less than 0.1 cannot be overcome by cooperativity, signal averaging, coherent detection, or by nonlinear dynamical systems. Sensory systems and possible effects on biological magnetite suggest paradigms for extreme sensitivity at lower frequencies, but there are no known radiofrequency (RF) analogues. At the molecular level, vibrational modes are so overdamped by water molecules that excitation of molecular modes below the far infrared cannot occur. Two RF mechanisms plausibly may affect biological matter under common exposure conditions. For frequencies below approximately 150 MHz, shifts in the rate of chemical reactions can be mediated by radical pairs and, at all frequencies, dielectric and resistive heating can raise temperature and increase the entropy of the affected biological system.