Introduction The Centers for Disease Control and Prevention (CDC) funded the Colorectal Cancer Screening Demonstration Program in 2005. To assess the feasibility of providing community-based colorectal cancer screening, CDC is conducting a multiple-case study as part of a larger evaluation effort. This article highlights key facilitators and challenges common to the five programs studied during the start-up period. Methods The multiple-case study that includes all five program sites is being conducted during the 3-year program as part of process evaluation efforts. Data collection for program start-up occurred during August 2005 through September 2006. Data include approximately 70 interviews with program staff and stakeholders, document review, and observations. Both case-specific and cross-case analyses were conducted. Results On the basis of the cross-case analysis, we identified four factors that facilitated program start-up and four factors that challenged program start-up. Facilitating factors included 1) pre-existing program infrastructure, 2) partnerships, 3) clinical expertise, and 4) program champions. Factors challenging program start-up included 1) contracts with endoscopists, 2) resources for treating medical complications of screening and for cancer treatment, 3) administrative barriers, and 4) resource limitations. Additionally, preplanning was critical, allowing programs to efficiently initiate activities once funds became available. Conclusion The most important facilitator identified was the ability to build on pre-existing infrastructure, which provided experienced staff, partnerships, and provider relationships, as well as aided program integration with other chronic disease programs. Results also suggest that substantial planning and partnership development can begin before funds are secured to implement a colorectal cancer screening program.