Heat shock proteins (HSPs) consist of a large group of proteins with negligible expressions under physiological conditions. Their expressions are highly induced under stress conditions and they are ubiquitously expressed in various tissues and organs. HSPs possess chaperone functions, thus facilitating the correct folding of proteins or peptides. In hepatocellular carcinoma (HCC), high expressions of HSPs are demonstrated in liver cancer tissues and are correlated clinically with the severity of tumors and poor outcomes of HCC patients. This property enables them to be used as diagnostic markers for the onset of HCC. Since their expressions are highly expressed in liver cancer conditions, inhibitors or antisense oligonucleotides of HSPs are postulated to serve as potential therapeutics in treating this liver malignancy. In this review, we will first introduce the HSP family and discuss the major signaling pathways involved for the activities of HSPs. In addition, the clinical applications of HSPs in liver cancer in the aspects of diagnosis and therapy will be summarized and discussed.