The emergence of SARS-CoV-2 variants threatens current vaccines and therapeutic antibodies and urgently demands powerful new therapeutics that can resist viral escape. Our goal has been to complement ongoing and long-term strategies to combat SARS-CoV-2 with inexpensive, superior and differentiated nanobody-based therapeutics that are insensitive to variants, immediately efficacious upon dosage (combating issues with vaccine immunity maintenance), and which can act as prophylactics to prevent infection. Nanobodies are “mini-antibodies”, recombinantly expressed antibody fragments that are ten times smaller than human antibodies. This small size is a critical advantage that enables (i) ready penetration of tissue, e.g. lung tissue, (ii) binding to viral antigens in sites that are sterically inaccessible to human antibodies, (iii) multiple different nanobodies to pack easily around one Spike trimer - endowing them with small molecule drug-like synergistic activity, and (iv) resistance to denaturation by harsh delivery mechanisms such as nebulization. We therefore generated a large nanobody repertoire to saturate the distinct and highly conserved available epitope space of SARS-CoV-2 spike, including the S1 receptor binding domain, N-terminal domain, and the S2 subunit, to identify new nanobody binding sites that may reflect novel mechanisms of viral neutralization. Structural mapping and functional assays show that indeed these highly stable monovalent nanobodies potently inhibit SARS-CoV-2 infection, display numerous neutralization mechanisms, are effective against emerging variants of concern, and are resistant to mutational escape. Rational combinations of these nanobodies that bind to distinct sites within and between spike subunits exhibit extraordinary synergy and suggest multiple tailored therapeutic and prophylactic strategies.