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Despite major scientific gains in important new knowledge about risks, biological processes, prevention practices, and advanced treatments for many forms of cancer, epidemiological evidence shows that cancer continues to evolve as an increasingly dangerous health issue responsible for unacceptably high levels of death and disability world-wide. Sadly, many major advances in cancer knowledge have not been adequately translated into needed personal and institutional actions that could significantly reduce cancer morbidity and mortality. Disseminating relevant and actionable cancer-related health information to those who are confronting cancer is essential for promoting needed cancer prevention and control. Cancer information dissemination efforts should clearly and persuasively communicate complex cancer information to diverse and often vulnerable audiences who desperately need relevant information about key cancer issues, including cancer prevention, early detection, informed diagnosis, cancer treatment, and successful cancer survivorship. Strategic health communication can build needed awareness about cancer risks and responses, promote trust, cooperation, and personal engagement, as well as support informed cancer decision-making. Communicating meaningfully with those who are at greatest risk from cancer, such as members of the most vulnerable segments of society who suffer from high levels of cancer morbidity and mortality, is especially important for promoting cancer prevention and control. However, effective communication with members of these high-risk populations is often fraught with communication barriers. Since many members of at-risk groups are among the poorest, lowest educated, and most disenfranchised members of society, they may encounter serious challenges to accessing and making sense of relevant health information. They often experience health literacy deficits that make it difficult for them to understand complex cancer information. Their cultural backgrounds may not support their following recommended cancer prevention and control health and life-style practices. They may experience economic limitations that make it difficult to access needed care, as well as to navigate complicated and bureaucratic health care systems. This review and policy article examines these serious challenges to effectively communicating relevant health information to vulnerable populations and suggests strategies for enhancing strategic use of communication messages and media to promote cancer prevention and control.