A single cell has the potential to kill an entire human being. Efforts to cure 
cancer are limited by survival of individual cancer cells despite immune 
surveillance and toxic therapies. Understanding the intricate network of 
pathways that maintain cellular homeostasis and mediate stress response or 
default into cell death is critical to the development of strategies to 
eradicate cancer. Autophagy, proteasomal degradation and the unfolded protein 
response (UPR) are cellular pathways that degrade and recycle excess or damaged 
proteins to maintain cellular homeostasis and survival. This review will discuss 
autophagy and how it is integrated with proteasomal degradation and UPR to 
govern cell fate through restoration of cellular homeostasis or default into the 
apoptotic cell death pathway. The first response of autophagy is macroautophagy, 
which sequesters cytoplasm including organelles inside double-membraned 
autophagosome vesicles that fuse with lysosomes to degrade and recycle the 
contents. Ubiquitination patterns on proteins targeted for degradation determine 
whether adapter proteins will bring them to developing autophagosomes or to 
proteasomes. Macroautophagy is followed by chaperone-mediated autophagy (CMA), 
in which Hsc70 (Heat shock cognate 70) selectively binds proteins with exposed 
KFERQ motifs and pushes them inside lysosomes through the LAMP-2A 
(Lysosome-associated membrane protein type 2A) receptor. These two processes and 
the lesser understood microautophagy, which involves direct engulfment of 
proteins into lysosomes, occur at basal and induced levels. Insufficient 
proteasome function or ER stress induction of UPR can induce autophagy, which 
can mitigate damage and stress. If this network is incapable of repairing the 
damage or overcoming continued stress, the default pathway of apoptosis is 
engaged to destroy the cell. Induction of macroautophagy by cancer therapeutics 
has led to clinical trials investigating combinations of HCQ 
(hydroxychloriquine) suppression of autophagy with apoptosis-inducing agents. 
Further study of the complex integration of autophagy, proteasomal degradation, 
UPR and apoptosis is likely to provide additional targets for our fight against 
cancer. This article is part of a Special Issue entitled "Apoptosis: Four 
Decades Later".