The rising rate of cancer-related diseases and mortality underscores the need for new approaches to directly target and fight cancer. This review summarizes one of these new promising treatments, the use of targeted chimeric proteins. Chimeric proteins are two proteins fused at the DNA level in such a way that, once expressed, they result in a single polypeptide chain consisting of two moieties: a targeting moiety (usually a cytokine or growth factor) and a killing moiety (usually a bacterial or plant toxin). Many chimeric proteins have been constructed and developed over the years for the treatment of a variety of malignancies and these molecules are the main scope of this review. Moreover, this review presents new approaches for battling cancer, such as recruiting the apoptotic machinery via chimeric proteins, the use of receptor-mediated delivery of toxin-DNA, or T-cells as vehicles for delivering immunotoxins, all of which are trying to develop specific, efficient, nontoxic and non-immunogenic reagents for targeted cancer treatment.