Recombinant DNA technologies have had a fundamental impact on drug discovery. The continuous emergence of unique gene assembly techniques resulted in the generation of a variety of therapeutic reagents such as vaccines, cancer treatment molecules and regenerative medicine precursors. With the advent of synthetic biology there is a growing need for precise and concerted assembly of multiple DNA fragments of various sizes, including chromosomes. In this article, we summarize the highlights of the recombinant DNA technology since its inception in the early 1970s, emphasizing on the most recent advances, and underscoring their principles, advantages and shortcomings. Current and prior cloning trends are discussed in the context of sequence requirements and scars left behind. Our opinion is that despite the remarkable progress that has enabled the generation and manipulation of very large DNA sequences, a better understanding of the cell's natural circuits is needed in order to fully exploit the current state-of-the-art gene assembly technologies.