An understanding of proton radiobiology is critical for optimization of both proton radiotherapy and assessment of carcinogenesis risk from space radiation. Although the physical aspects of proton beam radiobiology is well understood, the biological aspects, particularly the complex biological end points, have been underexplored and underexploited. This review focuses on the biological responses observed to date, across various scales, molecular, cellular and especially tissue levels. Proton-induced perturbations of gene expression, along with signaling and functional alterations in cell cycle, invasion, angiogenesis and metastasis are included. Particular emphasis is placed on differences noted in the literature between biological effects induced by protons and those induced by high-energy photons. An appreciation of the unique physical and biological characteristics of proton radiobiology should augment current strategies both to enhance therapeutic effectiveness and to quantify risk related to proton irradiation.