Computer aided design/manufacturing (CAD/CAM) technology has become an increasingly popular part of dentistry, which today also includes CAD/CAM resin-based composite (RBC) applications. Because CAD/CAM RBCs are much more difficult to bond, many methods and attachment materials are still being proposed, while the best application method is still a matter of debate. The present study therefore evaluates causal factors for a reliable long-term bond, which includes the surface preparation of the CAD/CAM RBC, aging and the type of luting material. The reliability of the bond was calculated, and supplemented by fractography to identify fracture mechanisms. Five categories of luting materials were used: (1) temporary zinc phosphate cement, (2) glass ionomer cement (GIC), (3) resin-modified GIC, (4) conventional adhesive resin cement (ARC), and (5) self-adhesive RC. Half of the CAD/CAM RBC surfaces (n = 200) were sandblasted (SB) with 50 µm aluminum oxide, while the other half remained untreated. Bond strength measurements of the 400 resulting specimens were carried out after 24 h (n = 200) or after additional aging (10,000 thermo-cycles between 5 and 55 °C) (n = 200). The data were statistically analyzed using one- and three-way ANOVA followed by Games-Howell post-hoc test (α = 0.05) and Weibull analysis. Aging resulted in a significant decrease in bond strength primarily for the conventional cements. The highest bond strengths and reliabilities were recorded for both ARCs. SB caused a significant increase in bond strength for most luting materials, but also caused microcracks in the CAD/CAM RBC. These microcracks might compromise the long-term reliability of the bond in vivo.