Next to their essential role as protein production factories, ribosomes serve as molecular sensors of cell stress. Stalled and collided ribosomes trigger specific stress signaling, including the ribotoxic stress response (RSR). The RSR is initiated by the mitogen-activated protein (MAP)-3 kinase ZAKα in response to a plethora of translational aberrations, leading to activation of the stress-activated MAP kinases p38 and jun N-terminal kinase (JNK). Recent insights have highlighted an important role for the RSR pathway in triggering programmed cell death processes, including apoptosis and pyroptosis, in a broad range of physiologically relevant conditions. In this review, we summarize recent work on known links between programmed and accidental ribosome toxicity, RSR signaling, and cell death.