This review article describes recently developed technologies in electron paramagnetic resonance (EPR) spectroscopy and imaging. Automatic control techniques used for a continuous-wave (CW) EPR spectrometer are discussed. These techniques can solve problems created by the motion of animals. Recent developments with time-domain EPR spectroscopy are also reported. Time-domain EPR spectroscopy is a technically challenging method because of the very short relaxation time that free radicals have in biological tissue. EPR imaging techniques are also reviewed, which are able to visualize free radicals in animal subjects non-invasively. Current status and future trends in the development of instruments for EPR spectroscopy and imaging are also presented, especially for biomedical applications. An important and powerful application of in vivo EPR spectroscopy and imaging is the detection of free radicals generated in biological specimens, which are so-called bioradicals. This article reviews these bioradicals, such as reactive oxygen species (ROS), free radicals generated from xenobiotics, metal ions, and common drugs, and it especially focuses on the direct-detection of bioradicals, rather than indirect detection. Drug-induced reaction mechanisms with hydrazine-based drugs, carcinogenic nitroso compounds, and prescription drugs for patients with hypertension (nifedipine) are discussed in detail based on in vivo studies with small animals. Metal-related reactions in vivo are also discussed with irons, chromate, and manganese.