Survivin expression is a poor prognostic marker in a number of cancers. Clinical trials are currently underway evaluating anti-sense oligonucleotides against Survivin, immunotherapy using Survivin primed dentritic cells and peptide mimics that block interaction of Survivin with Hsp90 resulting in loss of Survivin protein stability. Additional approaches using ribozymes against Survivin mRNA, or dominant-negative cDNA to block Survivin function are in pre-clinical stages. Like many genes, Survivin is alternately spliced and a number of new splice variants have recently been identified. Expression of some of these splice variants correlates with loss of steroid receptors as well as the tumor suppressor p53, in some cancers, suggesting that like wild-type Survivin, at least some of these splice variants may also have prognostic relevance. This review will focus on the current understanding of the function of Survivin splice variants and their expression and sub-cellular localization in normal and neoplastic tissues as well as critically evaluating the potential toxicity of the Survivin directed therapies and their predicted effect on the alternatively spliced Survivin isoforms