Candida albicans is a commensal organism that lives as benign member of the microflora of healthy individuals. In response to changes in the host immune status or microflora, C. albicans ceases to be a commensal organism and infects a variety of host tissues. The capacity to shift from a commensal to pathogenic state requires a coordinated metabolic response that triggers discrete developmental programs and that induce the expression of specific virulence traits. Several virulence traits have been described in C. albicans including adhesion, morphological and phenotypic switching, and the production of secreted hydrolytic enzymes. These attributes contribute to host tissue recognition, tissue invasion and colonization, as well as evasion of the host immune response. Recent experimental progress has illuminated some of the cellular processes that enable Candida cells to sense and respond to changes in the host environment. Similarly, cells of the host innate immune system are able to recognize invading C. albicans cells and induce a complex immune response that ultimately determines the clinical outcome of the infection. In this review we describe the current understanding of the events taking place during systemic infections of C. albicans. The interplay between defined pathogen and host specific responses are discussed. Additionally, we provide experimental data on the pathological consequences resulting from acute systemic infections of C. albicans in mice.