Interleukin (IL)-24, which is also known as the melanoma differentiation-associated gene-7 (mda-7) is a novel tumor suppressor and cytokine that belongs to the IL-10 family.  We and others have demonstrated that enforced expression of IL-24 leads to phosphorylation of the double-stranded RNA activated protein kinase R (PKR) and the protein kinase R-like endoplasmic reticulum (ER) kinase through ER stress response. This, in turn, activates c-Jun N-terminal protein kinase 1-3 signaling, with subsequent activation of Bax and other pro-apoptotic proteins, thereby inducing autophagy and apoptosis in cancer cells. In addition, IL-24 protein is ubiquitinated and degraded by the 26S proteasome and its inhibition results in IL-24 protein accumulation and enhances cell killing in cancer cells. The ubiquitin-proteasome and autophagy-lysosome systems are two important mechanisms in cellular protein degradation. Many studies have shown the importance of these protein degradation pathways in contributing to drug sensitivity and resistance in cancer cells. In this review,we focus on the molecular mechanisms of IL-24-mediated autophagy and apoptosis pathways leading to programmed cell death and as targets for improved cancer therapy.